Fistula grafts and related methods and systems useful for treating gastrointestinal and other fistulae

ABSTRACT

Described are medical graft products, systems, and methods useful for treating fistulae, particularly enterocutaneous fistulae. Certain products of the invention are configured to have portions residing in and around a primary fistula opening in a wall of the alimentary canal. One such product includes a biocompatible graft body which is configured to block at least the primary opening. The graft body includes a capping member connected to an elongate plug member. The capping member is configured to contact portions of the alimentary canal wall adjacent to the primary opening, and the elongate plug member is configured to extend into at least a portion of the fistula. A graft product of this sort may be particularly adapted to allow a portion of the capping member to be positioned alongside an exterior, lateral surface of the plug member, e.g., when placed in a delivery device lumen. Such a capping member may be hingedly or non-hingedly coupled to the elongate plug member.

BACKGROUND

The present invention relates generally to medical technology and inparticular aspects to devices and methods for treating fistulae andother passageways in the body.

As further background, there exist a variety of passages and other openspaces in the body which can be plugged, filled, blocked, etc. toprovide benefit to the patient. For example, it may be desirable toocclude a lumen or other open space in the vasculature (e.g., a bloodvessel such as a vein or artery). In some instances, a device isdeployed within the venous system, e.g., within the greater and/orlesser saphenous vein, to treat complications, such as a varicose veinconditions.

As well, it may be desirable to plug or otherwise fill a fistula. Avariety of fistulae can occur in humans. These fistulae can occur for avariety of reasons, such as but not limited to, as a congenital defect,as a result of inflammatory bowel disease, such as Chron's disease,irradiation, trauma, such as childbirth, or as a side effect from asurgical procedure. Further, several different types of fistulae canoccur, for example, urethro-vaginal fistulae, vesico-vaginal fistulae,tracheo-esophageal fistulae, gastro-cutaneous fistulae, and any numberof anorectal fistulae, such as recto-vaginal fistula, recto-vesicalfistulae, recto-urethral fistulae, or recto-prostatic fistulae.

The path which fistulae take, and their complexity, can vary. A fistulamay take a take a “straight line” path from a primary opening to asecondary opening, known as a simple fistula. Alternatively, a fistulamay comprise multiple tracts ramifying from a primary opening and havemultiple secondary openings. This is known as a complex fistula.

Anorectal fistulae can result from infection in the anal glands, whichare located around the circumference of the distal anal canal that formsthe anatomic 35 landmark known as the dentate line. Approximately 20-40such glands are found in humans. Infection in an anal gland can resultin an abscess. This abscess then can track through soft tissues (e.g.,through or around the sphincter muscles) into the perianal skin, whereit drains either spontaneously or surgically. The resulting void throughsoft tissue is known as a fistula. The internal or inner opening of thefistula, usually located at or near the dentate line, is known as theprimary opening. Any external or outer openings, which are usuallylocated in the perianal skin, are known as secondary openings.

One technique for treating a perianal fistula is to make an incisionadjacent the anus until the incision contacts the fistula and thenexcise the fistula from the anal 10 tissue. This surgical proceduretends to sever the fibers of the anal sphincter, and may causeincontinence. Other surgical treatment of fistulae involve passing afistula probe through the tract of the fistula in a blind manner, usingprimarily only tactile sensation and experience to guide to probe.Having passed the probe through the fistula tract, the overlying tissueis surgically divided. This is known as a fistulotomy. Since a variableamount of sphincter muscle is divided during the procedure, fistulotomyalso may result in impaired sphincter control, and even frankincontinence.

A gastrointestinal fistula is an abnormal passage that leaks contents ofthe stomach or the intestine (small or large bowel) to other organs,usually other parts of the intestine or the skin. For example,gastrojejunocolic fistulae include both enterocutaneous fistulae (thoseoccurring between the skin surface and the intestine, namely theduodenum, the jejunum, and the ileum) and gastric fistulae (thoseoccurring between the stomach and skin surface). Another type of fistulaoccurring in the gastrointestinal tract is an enteroenteral fistula,which refers to a fistula occurring between two parts of the intestine.Gastrointestinal fistulae can result in malnutrition and dehydrationdepending on their location in the gastrointestinal tract. They can alsobe a source of skin problems and infection. The majority of these typesof fistulae are the result of surgery (e.g., bowel surgery), althoughsometimes they can develop spontaneously or from trauma, especiallypenetrating traumas such as stab wounds or gunshot wounds. Inflammatoryprocesses, such as infection or inflammatory bowel disease (Crohn'sdisease), may also cause gastrointestinal fistulae. In fact, Crohn'sdisease is the most common primary bowel disease leading toenterocutaneous fistulae, and surgical treatment may be difficultbecause additional enterocutaneous fistulae develop in many of thesepatients postoperatively.

Treatment options for gastrointestinal fistulae vary. Depending on theclinical situation, patients may require IV nutrition and a period oftime without food to allow the fistula time to close on its own. Indeed,nonsurgical therapy may allow spontaneous closure of the fistula,although this can be expected less than 30% of the time according to oneestimate. A variable amount of time to allow spontaneous closure offistulae has been recommended, ranging from 30 days to 6 to 8 weeks.During this preoperative preparation, external control of the fistuladrainage prevents skin disruption and provides guidelines for fluid andelectrolyte replacement. In some cases, surgery is necessary to removethe segment of intestine involved in a non-healing fistula.

When surgery is deemed necessary, one operation for fistula closure isresection of the fistula-bearing segment and primary end-to-endanastamosis. The anastomosis may be reinforced by greater momentum or aserosal patch from adjacent small bowel. Still other methods fortreating fistulae involve injecting sclerosant or sealant (e.g.,collagen or fibrin glue) into the tract of the fistula to block thefistula. Closure of a fistula using a sealant is typically performed asa two-stage procedure, including a first-stage seton placement andinjection of the fibrin glue several weeks later. This allows residualinfection to resolve and to allow the fistula tract to “mature” prior toinjecting a sealant. If sealant or sclerosant were injected as aone-stage procedure, into an “unprepared” or infected fistula, this maycause a flare-up of the infection and even further abscess formation.

There remain needs for improved and/or alternative devices, systems andmethods for treating fistulae and other sites in the body. The presentinvention is addressed to those needs.

SUMMARY

The present invention provides, in certain aspects, unique medicalproducts for treating fistulae having at least a primary opening in thealimentary canal and a fistula tract. Certain embodiments of theinvention relate to fistula grafts which are configured to have portionsresiding in and around a primary fistula opening, such as agastrointestinal fistula primary opening. For example, some inventivefistula grafts include a biocompatible graft body which is configured toblock at least the primary fistula opening, wherein the graft bodycomprises a capping member and an elongate plug member, which extendsfrom the capping member. The capping member is configured to contactportions of the alimentary canal wall adjacent to the primary opening,and the elongate plug member is configured to extend into at least aportion of the fistula tract. The capping member and the elongate plugmember are formed separately and then coupled to one another (e g,hingedly coupled with a suture) or otherwise suitably united, oralternatively, the two may be formed as a single unit for example, froma single piece of material or other object. In this regard, each of thetwo members can exhibit any suitable size, shape, and configuration, andmay be formed with one or more of a variety of suitable biocompatiblematerials. In some forms, the graft body is configured to seal off orsubstantially seal off the primary fistula opening when suitablydeployed. The capping member and/or the elongate plug member, in certainaspects, comprise an expandable element, for example, an expandablematerial such as a compressed sponge material and/or an expandabledevice such as a resilient wire frame. In preferred aspects, the cappingmember and/or the elongate plug member comprise a remodelable,angiogenic material, for example, a remodelable extracellular matrixmaterial such as submucosa. Further, the medical graft product, in someforms, can include a suture in association with the graft body. Thissuture can be used, for example, to draw the product into the fistulaprimary opening and/or to secure the product to soft tissues at or neara secondary opening in the fistula.

In one particular embodiment, the invention provides a method fortreating a fistula having a primary opening in a wall of the alimentarycanal and a fistula tract. This method comprises (i) providing a medicalgraft product including a biocompatible graft body that is configured toblock at least the primary fistula opening, wherein the graft bodyincludes a capping member and an elongate plug member extending from thecapping member; said capping member being hingedly coupled to saidelongate plug member and (ii) implanting the medical graft productwithin a patient so that the capping member contacts portions of thealimentary canal wall adjacent to the primary opening, and the elongateplug member extends into at least a portion of the fistula tract. Incertain aspects, a suitably configured medical graft product isimplanted so as to seal off or substantially seal off the primaryopening. Further, the medical graft product may include an anchoringadaptation useful for maintaining the capping member in contact withportions of the alimentary canal wall adjacent to the primary opening.Suitable anchoring adaptations include but are not limited to adhesives(e.g., dried, reversible adhesives), barbs, hooks, sutures, and thelike.

In another embodiment, the present invention provides a medical graftproduct useful for treating a fistula having a primary opening in a wallof the alimentary canal and a fistula tract. This medical graft productincludes a biocompatible graft body configured to block at least theprimary opening of the fistula. The graft body is comprised of a cappingmember and an elongate plug member. The plug member has a proximal anddistal end, with a lumen extending therethrough. The capping memberextends from the distal end of the elongate plug member, and isconfigured to contact portions of the alimentary canal wall adjacent tothe primary opening. The elongate plug member is configured to extendinto at least a portion of the fistula tract, and includes a pluralityof passages. The longitudinal axis of each passage runs through the plugmember lumen to allow communication between opposing sides of theexterior surface of the elongate plug member.

Another aspect of the present invention provides a graft product fortreating a fistula, which is comprised of a graft body configured toreside in a tract of the fistula, and a capping member configured tocontact tissues adjacent an opening of the fistula. The capping memberis connected to an end region of the graft body, and includes a portionpositionable along an exterior lateral surface of the graft body.

In yet another aspect, the invention provides a medical graft productthat is comprised of a capping member, and an elongate graft bodyextending from the capping member. The capping member includes a portionpositionable over an exterior lateral surface of the elongate graftbody. This portion is conformable to the exterior lateral surface of theelongate graft body.

The present invention provides, in another embodiment, an apparatus fortreating a fistula having at least an opening in a bodily structure walland a fistula tract extending from the opening. This apparatus comprisesa delivery device having a lumen communicating with a distal endopening, wherein the delivery device is configured for passage throughthe fistula tract and the opening. The apparatus also comprises amedical graft device removably positioned in the delivery device lumen.The medical graft device is comprised of a biocompatible graft body, andincludes a capping member and an elongate plug member. The cappingmember is configurable to a first condition permitting at least part ofthe capping member to be positioned along an exterior lateral surface ofthe elongate plug member when in the delivery device lumen. The elongateplug member extends from the capping member, and is effective to fill atleast a portion of the fistula tract.

Another aspect of the present invention provides a method for implantinga medical device in a patient. In one method step, an implantablemedical device is provided. This medical device comprises a device body,a first imageable component and a second imageable component. The devicebody includes a deformable anchoring component that is deformable from afirst condition to a second condition. In another method step, themedical device is delivered to an implantation site in the patient. Inanother step, the anchoring component is deformed from the firstcondition to the second condition, wherein the first imageable componentchanges position relative to the second imageable component. In anotherstep, the change in position of the first imageable component relativeto the second imageable component is visualized.

In another embodiment, the present invention provides an implantablemedical device. This medical device comprises a device body, a firstimageable component and a second imageable component. The device bodyincludes a deformable anchoring component that is deformable from afirst condition to a second condition. The first imageable component andthe second imageable component are arranged such that upon deformationof the anchoring component from the first condition to the secondcondition, the position of the first imageable component relative to thesecond imageable component changes.

In another illustrative embodiment, the invention provides a medicalgraft device useful for treating a fistula having at least a primaryopening in a bodily structure wall and a fistula tract extending fromthe primary opening. This medical graft device comprises a biocompatiblegraft body that includes a capping member and an elongate plug member.The elongate plug member extends from the capping member, and isconfigured to fill at least a portion of the fistula tract. This medicalgraft device also includes a retaining system for retaining the cappingmember in association with the plug member. The retaining systemincludes a first pin or other retaining member and a second pin or otherretaining member. The first pin is configured for insertion through anaperture in the capping member and into a generally longitudinal, firstpassage in the plug member. The second pin is configured for insertioninto a generally lateral, second passage in the plug member. The firstpin and the second pin are configured to engage one another in the plugmember for maintaining the first pin and the second pin in the plugmember.

An additional embodiment of the present invention provides a medicalgraft device useful for treating a fistula having at least a primaryopening in a bodily structure wall and a fistula tract extending fromthe primary opening. This medical graft device comprises a biocompatiblegraft body including a capping member and an elongate member thatextends from the capping member. The capping member includes aperipheral support frame and a radiopaque component that is positionedto the interior of the support frame. The elongate member is configuredto extend through the fistula tract when the graft device is implanted.

In another aspect, the invention provides a method for treating afistula having at least a primary opening in a bodily structure wall anda fistula tract extending from the primary opening. One step in thismethod includes providing a medical graft device that includes abiocompatible graft body. This graft body includes a capping member andan actuating member that extends from the capping member. The cappingmember is deformable to a deformed condition that includes anexternalized radiopaque portion and an internalized radiopaque portion.The actuating member is configured to extend through the fistula tractwhen the graft device is implanted, and is actuatable to convert thecapping member to the deformed condition. In another method step, themedical graft device is positioned in a patient such that the cappingmember contacts portions of the bodily structure wall adjacent to theprimary opening, and the actuating member extends into at least aportion of the fistula tract. In another method step, the actuatingmember is pulled in a direction generally away from the primary openingso as to convert the capping member to the deformed condition. In thisdeformed condition, the externalized radiopaque portion residesexternally of the fistula tract, and the internalized radiopaque portionresides within the fistula tract and is spaced a distance from theexternalized radiopaque portion.

In yet another embodiment, the present invention provides a medicalgraft device useful for treating a fistula having at least a primaryopening in a bodily structure wall and a fistula tract extending fromthe primary opening. This medical graft device comprises a biocompatiblegraft body that includes a capping member and an actuating memberextending from the capping member. The capping member is deformable to adeformed condition that including an externalized radiopaque portion andan internalized radiopaque portion. The externalized radiopaque portionis configured to reside externally of the fistula tract when the graftdevice is implanted and the capping member is deformed. The internalizedradiopaque portion is configured to reside within the fistula tract andbe spaced a distance from the externalized radiopaque portion when thegraft device is implanted and the capping member is deformed. Theactuating member is configured to extend through the fistula tract whenthe graft device is implanted, and is actuatable to convert the cappingmember to the deformed condition.

Other objects, embodiments, forms, features, advantages, aspects, andbenefits of the present invention shall become apparent from thedetailed description and drawings included herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a perspective view of an illustrative medical graft productin its original configuration including an elongate plug member and acapping member hingedly coupled thereto.

FIG. 1B is a perspective view of the medical graft product illustratedin FIG. 1A where the capping member is folded over the elongate plugmember to provide an intermediate configuration.

FIG. 1C is a perspective view of the medical graft product illustratedin FIG. 1B where the capping member is rolled around the elongate plugmember to provide an implantable configuration.

FIG. 1D is a perspective view of the medical graft product in itsimplantable configuration as illustrated in FIG. 1C where the cappingmember is folded and rolled over the elongate plug member and isinserted into a sheath for delivery.

FIG. 1E is a perspective view of an illustrative medical graft productincluding an elongate body, a capping member, and a pull tether.

FIG. 2A is a perspective view of a support frame useful in the presentinvention.

FIG. 2B provides a perspective view of a capping member of the presentinvention.

FIG. 3A is a perspective view of a medical graft device of theinvention.

FIG. 3B shows the medical graft device of FIG. 3A implanted within apatient.

FIG. 4A is a perspective view of a medical graft device of theinvention.

FIG. 4B is a partial, perspective view of the medical graft device ofFIG. 4A positioned in a delivery device lumen.

FIG. 5 provides a perspective view of a capping member of the presentinvention.

FIG. 6 provides a partial, side view of granting device according to oneembodiment of the present invention.

FIG. 7 shows the grafting device of FIG. 6 implanted within a patient.

FIG. 8A shows a perspective view of a retaining system component of theinvention.

FIG. 8B shows a perspective view of another retaining system componentof the invention.

DETAILED DESCRIPTION

As disclosed above, in certain aspects, the present invention providesunique medical graft products and methods useful for treating fistulaehaving at least a fistula tract and a primary opening in the alimentarycanal or other similar voids in bodily tissues. For example, someinventive graft products include a biocompatible graft body which isconfigured to block at least the primary fistula opening, wherein thegraft body includes a capping member and an elongate plug memberextending from the capping member. The capping member is configured tocontact portions of the alimentary canal wall adjacent to the primaryopening, and the elongate plug member is configured to extend into atleast a portion of the fistula tract. The elongate plug member and thecapping member are preferably formed separately and then coupled to oneanother by a coupling element. The biocompatible graft body preferablycomprises a remodelable material, for example, a remodelableextracellular matrix material such as submucosa. The invention alsoprovides methods utilizing such graft products and medical products thatinclude such graft products enclosed within sterile packaging.

Graft materials useful in the medical graft products of the presentinvention can include any suitable biocompatible material. Generally,the graft materials may include a remodelable and/or resorbablematerial, such as a resorbable synthetic material or a naturally derivedresorbable or remodelable material. Additionally, graft materials caninclude any other suitable naturally derived or any other suitablenonresorbable synthetic material, or any combination of any of the abovesuch biocompatible materials. Such biocompatible materials that are atleast bioresorbable will provide advantage in certain embodiments of theinvention, with materials that are bioremodelable or otherwise tissueinductive so as to promote cellular invasion and ingrowth providingparticular advantage. Illustratively, remodelable materials may be usedin this context to promote cellular growth within the graft materials topromote healing and closure of at least the primary opening of afistula.

Suitable materials for use in the invention can be provided bycollagenous extracellular matrix (ECM) materials, including but notlimited to those possessing biotropic or remodelable properties,including in certain forms angiogenic collagenous extracellular matrixmaterials. For example, suitable collagenous materials include ECMmaterials such as those comprising submucosa, renal capsule membrane,dermal collagen (including processed dermal collagen from humancadavers, which can be used as allograft in humans), dura mater,pericardium, facia lata, serosa, peritoneum, or basement membranelayers, including liver basement membrane. Suitable submucosa materialsfor these purposes include, for instance, intestinal submucosa,including small intestinal submucosa, stomach submucosa, urinary bladdersubmucosa, and uterine submucosa. Some preferred medical graft productsof the invention will include submucosa, such as submucosa derived froma warm-blooded vertebrate. Mammalian submucosa materials are preferred.In particular, submucosa materials derived from animals raised for meator other product production, e.g. pigs, cattle or sheep, will beadvantageous. Porcine submucosa provides a particularly preferredmaterial for use in the present invention, especially porcine smallintestine submucosa (SIS), more especially porcine small intestinesubmucosa retaining substantially its native cross-linking.

The submucosa or other ECM material can be derived from any suitableorgan or other biological structure, including for example submucosaderived from the alimentary, respiratory, intestinal, urinary or genitaltracts of warm-blooded vertebrates. Collagenous matrices comprisingsubmucosa (potentially along with other associated tissues) useful inthe present invention can be obtained by harvesting such tissue sourcesand delaminating the submucosa-containing matrix from smooth musclelayers, mucosal layers, and/or other layers occurring in the tissuesource. For additional information concerning submucosa useful incertain embodiments of the present invention, and its isolation andtreatment, reference can be made, for example, to U.S. Pat. Nos.4,902,508, 5,554,389, 5,993,844, 6,206,931, and 6,099,567.

Submucosa-containing or other ECM materials of the present invention canbe derived from any suitable organ or other tissue source, usuallysources containing connective tissues. The ECM materials processed foruse in the invention will typically include abundant collagen, mostcommonly being constituted at least about 80% by weight collagen on adry weight basis. Such naturally-derived ECM materials will for the mostpart include collagen fibers that are non-randomly oriented, forinstance occurring as generally uniaxial or multi-axial but regularlyoriented fibers. When processed to retain native bioactive factors, theECM material can retain these factors interspersed as solids between,upon and/or within the collagen fibers. Particularly desirablenaturally-derived ECM materials for use in the invention will includesignificant amounts of such interspersed, non-collagenous solids thatare readily ascertainable under light microscopic examination. Suchnon-collagenous solids can constitute a significant percentage of thedry weight of the ECM material in certain inventive embodiments, forexample at least about 1%, at least about 3%, and at least about 5% byweight in various embodiments of the invention.

The submucosa or other ECM material used in the present invention mayalso exhibit an angiogenic character and thus be effective to induceangiogenesis in a host engrafted with the material. In this regard,angiogenesis is the process through which the body makes new bloodvessels to generate increased blood supply to tissues. Thus, angiogenicmaterials, when contacted with host tissues, promote or encourage theformation of new blood vessels. Methods for measuring in vivoangiogenesis in response to biomaterial implantation have recently beendeveloped. For example, one such method uses a subcutaneous implantmodel to determine the angiogenic character of a material. See, C.Heeschen et al., Nature Medicine 7 (2001), No. 7, 833-839. When combinedwith a fluorescence microangiography technique, this model can provideboth quantitative and qualitative measures of angiogenesis intobiomaterials. C. Johnson et al., Circulation Research 94 (2004), No. 2,262-268.

As prepared and used, the submucosa material or any other ECM materialmay optionally retain and/or otherwise include growth factors or otherbioactive components native to the source tissue. For example, thesubmucosa or other ECM material may retain one or more growth factorssuch as basic fibroblast growth factor (FGF-2), transforming growthfactor beta (TGF-beta), epidermal growth factor (EGF), cartilage derivedgrowth factor (CDGF) and/or platelet derived growth factor (PDGF). Aswell, submucosa or other ECM material used in certain embodiments of theinvention may retain or include other biological materials such as butnot limited to proteins, glycoproteins, proteoglycans, andglycosaminoglycans. For example, ECM materials may include heparin,heparin sulfate, hyaluronic acid, fibronectin, cytokines and the like.Thus, generally speaking, the submucosa or other ECM material may retainor otherwise include a bioactive component that induces, directly orindirectly, a cellular response such as a change in cell morphology,proliferation, growth, protein or gene expression.

Further, in addition or as an alternative to the inclusion of suchnative bioactive components, non-native bioactive components such asthose synthetically produced by recombinant technology or other methods,may be incorporated into the submucosa or other ECM material. Thesenon-native bioactive components may be naturally-derived orrecombinantly produced proteins that correspond to those nativelyoccurring in the ECM material, but perhaps of a different species (e.g.human proteins applied to collagenous ECMs from other animals, such aspigs). The nonnative bioactive components may also be drug substances.Illustrative drug substances that may be incorporated into and/or ontothe ECM material can include, for example, antibiotics and/orthrombus-promoting substances such as blood clotting factors, e.g.thrombin, fibrinogen, and the like. These substances may be applied tothe ECM material as a premanufactured step, immediately prior to theprocedure (e.g. by soaking the material in a solution containing asuitable antibiotic such as cefazolin), or during or after engraftmentof the ECM material within the patient.

Medical graft products of the invention can include xenograft material(i.e., cross-species material, such as tissue material from a non-humandonor to a human recipient), allograft material (i.e., interspeciesmaterial, with tissue material from a donor of the same species as therecipient), and/or autograft material (i.e., where the donor and therecipient are the same individual). Further, any exogenous bioactivesubstance incorporated into an ECM material may be from the same speciesof animal from which the ECM material was derived (e.g. autologous orallogenic relative to the ECM material) or may be from a differentspecies from the ECM material source (xenogenic relative to the ECMmaterial). In certain embodiments, ECM material will be xenogenicrelative to the patient receiving the graft, and any added exogenousmaterial(s) will be from the same species (e.g. autologous or allogenic)as the patient receiving the graft. Illustratively, human patients maybe treated with xenogenic ECM materials (e.g. porcine-, bovine- orovine-derived) that have been modified with exogenous human material(s)as described herein, those exogenous materials being naturally derivedand/or recombinantly produced.

Submucosa or other ECM material used in certain embodiments of theinvention is preferably highly purified, for example, as described inU.S. Pat. No. 6,206,931 to Cook et al. Thus, preferred ECM material willexhibit an endotoxin level of less than about 12 endotoxin units (EU)per gram, more preferably less than about 5 EU per gram, and mostpreferably less than about 1 EU per gram. As additional preferences, thesubmucosa or other ECM material may have a bioburden of less than about1 colony forming units (CFU) per gram, more preferably less than about0.5 CFU per gram. Fungus levels are desirably similarly low, for exampleless than about 1 CFU per gram, more preferably less than about 0.5 CFUper gram. Nucleic acid levels are preferably less than about 5 μg/mg,more preferably less than about 2 μg/mg, and virus levels are preferablyless than about 50 plaque forming units (PFU) per gram, more preferablyless than about 5 PFU per gram. The ECM material used in certainembodiments of the invention is preferably disinfected with an oxidizingagent, particularly a peracid, such as peracetic acid. These andadditional properties of submucosa or other ECM materials taught in U.S.Pat. No. 6,206,931 may be characteristic of the submucosa used incertain embodiments of the present invention.

A typical layer thickness for an as-isolated submucosa or other ECMtissue layer used in the invention ranges from about 50 to about 250microns when fully hydrated, more typically from about 50 to about 200microns when fully hydrated, although isolated layers having otherthicknesses may also be obtained and used. These layer thicknesses mayvary with the type and age of the animal used as the tissue source. Aswell, these layer thicknesses may vary with the source of the tissueobtained from the animal source.

ECM materials used in the invention may be free or essentially free ofadditional, non-native crosslinking, or may contain additionalcrosslinking. Such additional crosslinking may be achieved byphoto-crosslinking techniques, by chemical crosslinkers, or by proteincrosslinking induced by dehydration or other means. However, becausecertain crosslinking techniques, certain crosslinking agents, and/orcertain degrees of crosslinking can destroy the remodelable propertiesof a remodelable material, where preservation of remodelable propertiesis desired, any crosslinking of the remodelable ECM material can beperformed to an extent or in a fashion that allows the material toretain at least a portion of its remodelable properties. Chemicalcrosslinkers that may be used include for example aldehydes such asglutaraldehydes, diimides such as carbodiimides, e.g.,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, ribose orother sugars, acyl-azide, sulfo-N-hydroxysuccinamide, or polyepoxidecompounds, including for example polyglycidyl ethers such asethyleneglycol diglycidyl ether, available under the trade name DENACOLEX810 from Nagese Chemical Co., Osaka, Japan, and glycerol polyglycerolether available under the trade name DENACOL EX 313 also from NageseChemical Co. Typically, when used, polyglycerol ethers or otherpolyepoxide compounds will have from 2 to about 10 epoxide groups permolecule.

Turning now to a discussion of drying techniques that can be useful incertain embodiments of the invention, drying by evaporation, or airdrying, generally comprises drying a partially or completely hydratedremodelable material by allowing the hydrant to evaporate from thematerial. Evaporative cooling can be enhanced in a number of ways, suchas by placing the material in a vacuum, by blowing air over thematerial, by increasing the temperature of the material, by applying ablotting material during evaporation, or by any other suitable means orany suitable combination thereof. The amount of void space or openmatrix structure within an ECM material that has been dried byevaporation is typically more diminished than, for example, an ECMmaterial dried by lyophilization as described below.

A suitable lyophilization process can include providing an ECM materialthat contains a sufficient amount of hydrant such that the voids in thematerial matrix are filled with the hydrant. The hydrant can compriseany suitable hydrant known in the art, such as purified water or sterilesaline, or any suitable combination thereof. Illustratively, thehydrated material can be placed in a freezer until the material andhydrant are substantially in a frozen or solid state. Thereafter, thefrozen material and hydrant can be placed in a vacuum chamber and avacuum initiated. Once at a sufficient vacuum, as is known in the art,the frozen hydrant will sublime from the material, thereby resulting ina dry remodelable material.

In alternative embodiments, a hydrated ECM material can be lyophilizedwithout a separately performed pre-freezing step. In these embodiments,a strong vacuum can be applied to the hydrated material to result inrapid evaporative cooling which freezes the hydrant within the ECMmaterial. Thereafter, the frozen hydrant can sublime from the materialthereby drying the ECM material. Desirably, an ECM material that isdried via lyophilization maintains a substantial amount of the voidspace, or open matrix structure, that is characteristic of the harvestedECM material.

Drying by vacuum pressing generally comprises compressing a fully orpartially hydrated remodelable material while the material is subject toa vacuum. One suitable method of vacuum pressing comprises placing aremodelable material in a vacuum chamber having collapsible walls. Asthe vacuum is established, the walls collapse onto and compress thematerial until it is dry Similar to evaporative drying, when aremodelable material is dried in a vacuum press, more of the material'sopen matrix structure is diminished or reduced than if the material wasdried by lyophilization.

In certain aspects, the invention provides medical products including amultilaminate material. Such multilaminate materials can include aplurality of ECM material layers bonded together, a plurality of non-ECMmaterials bonded together, or a combination of one or more ECM materiallayers and one or more non-ECM material layers bonded together. To forma multilaminate ECM material, for example, two or more ECM segments arestacked, or one ECM segment is folded over itself at least one time, andthen the layers are fused or bonded together using a bonding technique,such as chemical cross-linking or vacuum pressing during dehydratingconditions. An adhesive, glue or other bonding agent may also be used inachieving a bond between material layers. Suitable bonding agents mayinclude, for example, collagen gels or pastes, gelatin, or other agentsincluding reactive monomers or polymers, for example cyanoacrylateadhesives. As well, bonding can be achieved or facilitated between ECMmaterial layers using chemical cross-linking agents such as thosedescribed above. A combination of one or more of these withdehydration-induced bonding may also be used to bond ECM material layersto one another.

A variety of dehydration-induced bonding methods can be used to fusetogether portions of an ECM material. In one preferred embodiment,multiple layers of ECM material are compressed under dehydratingconditions. In this context, the term “dehydrating conditions” isdefined to include any mechanical or environmental condition whichpromotes or induces the removal of water from the ECM material. Topromote dehydration of the compressed ECM material, at least one of thetwo surfaces compressing the matrix structure can be water permeable.Dehydration of the ECM material can optionally be further enhanced byapplying blotting material, heating the matrix structure or blowing air,or other inert gas, across the exterior of the compressed surfaces. Oneparticularly useful method of dehydration bonding ECM materials islyophilization.

Another method of dehydration bonding comprises pulling a vacuum on theassembly while simultaneously employing the vacuum to press the assemblytogether. Again, this method is known as vacuum pressing. During vacuumpressing, dehydration of the ECM materials in forced contact with oneanother effectively bonds the materials to one another, even in theabsence of other agents for achieving a bond, although such agents canbe used while also taking advantage at least in part of thedehydration-induced bonding. With sufficient compression anddehydration, the ECM materials can be caused to form a generally unitaryECM structure.

It is advantageous in some aspects of the invention to perform dryingand other operations under relatively mild temperature exposureconditions that minimize deleterious effects upon any ECM materialsbeing used, for example native collagen structures and potentiallybioactive substances present. Thus, drying operations conducted with noor substantially no duration of exposure to temperatures above humanbody temperature or slightly higher, say, no higher than about 38° C.,will preferably be used in some forms of the present invention. Theseinclude, for example, vacuum pressing operations at less than about 38°C., forced air drying at less than about 38° C., or either of theseprocesses with no active heating—at about room temperature (about 25°C.) or with cooling. Relatively low temperature conditions also, ofcourse, include lyophilization conditions.

In additional embodiments, medical graft products of the invention canbe made from ECM's or other collagenous materials that have beensubjected to processes that expand the materials. In certain forms, suchexpanded materials can be formed by the controlled contact of an ECMmaterial with one or more alkaline substances until the materialexpands, and the isolation of the expanded material. Illustratively, thecontacting can be sufficient to expand the ECM material to at least 120%of (i.e. 1.2 times) its original bulk volume, or in some forms to atleast about two times its original volume. Thereafter, the expandedmaterial can optionally be isolated from the alkaline medium, e.g. byneutralization and/or rinsing. The collected, expanded material can beused in any suitable manner in the preparation of a graft device.Illustratively, the expanded material can be enriched with bioactivecomponents, dried, and/or molded, etc., in the formation of a graftconstruct to a desired shape or configuration. In certain embodiments, adried graft construct formed with the expanded ECM material can behighly compressible (or expandable) such that the material can becompressed for delivery, such as from within the lumen of a cannulateddelivery device, and thereafter expand upon deployment from the deviceso as to become anchored within a patient and/or cause closure of atract within the patient.

Expanded collagenous or ECM materials can be formed by the controlledcontact of a collagenous or ECM material with an aqueous solution orother medium containing sodium hydroxide. Alkaline treatment of thematerial can cause changes in the physical structure of the materialthat in turn cause it to expand. Such changes may include denaturationof the collagen in the material. In certain embodiments, it is preferredto expand the material to at least about three, at least about four, atleast about 5, or at least about 6 or even more times its original bulkvolume. The magnitude of the expansion is related to several factors,including for instance the concentration or pH of the alkaline medium,exposure time, and temperature used in the treatment of the material tobe expanded.

ECM materials that can be processed to make expanded materials caninclude any of those disclosed herein or other suitable ECM's. Typicalsuch ECM materials will include a network of collagen fibrils havingnaturally-occurring intramolecular cross links and naturally-occurringintermolecular cross links. Upon expansion processing as describedherein, the naturally-occurring intramolecular cross links andnaturally-occurring intermolecular cross links can be retained in theprocessed collagenous matrix material sufficiently to maintain thecollagenous matrix material as an intact collagenous sheet material;however, collagen fibrils in the collagenous sheet material can bedenatured, and the collagenous sheet material can have analkaline-processed thickness that is greater than the thickness of thestarting material, for example at least 120% of the original thickness,or at least twice the original thickness.

Illustratively, the concentration of the alkaline substance fortreatment of the remodelable material can be in the range of about 0.5to about 2 M, with a concentration of about 1 M being more preferable.Additionally, the pH of the alkaline substance can in certainembodiments range from about 8 to about 14. In preferred aspects, thealkaline substance will have a pH of from about 10 to about 14, and mostpreferably of from about 12 to about 14.

In addition to concentration and pH, other factors such as temperatureand exposure time will contribute to the extent of expansion, asdiscussed above. In this respect, in certain variants, the exposure ofthe collagenous material to the alkaline substance is performed at atemperature of about 4 to about 45° C. In preferred embodiments, theexposure is performed at a temperature of about 25 to about 40° C., with37° C. being most preferred. Moreover, the exposure time can range fromat least about one minute up to about 5 hours or more. In someembodiments, the exposure time is about 1 to about 2 hours. In aparticularly preferred embodiment, the collagenous material is exposedto a 1 M solution of NaOH having a pH of 14 at a temperature of about37° C. for about 1.5 to 2 hours. Such treatment results in collagendenaturation and a substantial expansion of the remodelable material.Denaturation of the collagen matrix of the material can be observed as achange in the collagen packing characteristics of the material, forexample a substantial disruption of a tightly bound collagenous networkof the starting material. A non-expanded ECM or other collagenousmaterial can have a tightly bound collagenous network presenting asubstantially uniform, continuous surface when viewed by the naked eyeor under moderate magnification, e.g. 100× magnification. Conversely, anexpanded collagenous material can have a surface that is quitedifferent, in that the surface is not continuous but rather presentscollagen strands or bundles in many regions that are separated bysubstantial gaps in material between the strands or bundles when viewedunder the same magnification, e.g. about 100×. Consequently, an expandedcollagenous material typically appears more porous than a correspondingnon-expanded collagenous material. Moreover, in many instances, theexpanded collagenous material can be demonstrated as having increasedporosity, e.g. by measuring for an increased permeability to water orother fluid passage as compared to the non-treated starting material.The more foamy and porous structure of an expanded ECM or othercollagenous material can allow the material to be cast or otherwiseprepared into a variety of sponge or foam shapes for use in thepreparation of medical materials and devices. It can further allow forthe preparation of constructs that are highly compressible and whichexpand after compression. Such properties can be useful, for example,when the prepared graft construct is to be compressed and loaded into adeployment device (e.g. a lumen thereof) for delivery into a patient,and thereafter deployed to expand at the implant site.

After such alkaline treatments, the material can be isolated from thealkaline medium and processed for further use. Illustratively, thecollected material can be neutralized and/or rinsed with water to removethe alkalinity from the material, prior to further processing of thematerial to form a graft construct.

A starting ECM material (i.e., prior to treatment with the alkalinesubstance) can optionally include a variety of bioactive or othernon-collagenous components including, for example, growth factors,glycoproteins, glycosaminoglycans, proteoglycans, nucleic acids, andlipids. Treating the material with an alkaline substance may reduce thequantity of one, some or all of such non-collagenous componentscontained within the material. In certain embodiments, controlledtreatment of the remodelable material with an alkaline substance will besufficient to create a remodelable collagenous material which issubstantially devoid of nucleic acids and lipids, and potentially alsoof growth factors, glycoproteins, glycosaminoglycans, and proteoglycans.

In certain embodiments, one or more bioactive components, exogenous orendogenous, for example, similar to those removed from an expandedmaterial during alkaline processing, can be returned to the material.For example, an expanded material can include a collagenous materialwhich has been depleted of nucleic acids and lipids, but which has beenreplenished with growth factors, glycoproteins, glycosaminoglycans,and/or proteoglycans. These bioactive components can be returned to thematerial by any suitable method. For instance, in certain forms a tissueextract, such as is discussed in U.S. Pat. No. 6,375,989 which is herebyincorporated herein by reference in its entirety, containing thesecomponents can be prepared and applied to an expanded collagenousmaterial. In one embodiment, the expanded collagenous material can beincubated in a tissue extract for a sufficient time to allow bioactivecomponents contained therein to associate with the expanded collagenousmaterial. The tissue extract may, for example, be obtained fromnon-expanded collagenous tissue of the same type used to prepare theexpanded material. Other means for returning or introducing bioactivecomponents to an expanded remodelable collagenous material includespraying, impregnating, dipping, etc. as known in the art. By way ofexample, an expanded collagenous material may be modified by theaddition of one or more growth factors such as basic fibroblast growthfactor (FGF-2), transforming growth factor beta (TGF beta), epidermalgrowth factor (EGF), platelet derived growth factor (PDGF), and/orcartilage derived growth factor (CDGF). As well, other biologicalcomponents may be added to an expanded collagenous material, such asheparin, heparin sulfate, hyaluronic acid, fibronectin and the like.Thus, generally speaking, an expanded collagenous material may include abioactive component that induces, directly or indirectly, a cellularresponse such as a change in cell morphology, proliferation, growth,protein or gene expression similar to a non-expanded collagenousmaterial.

Expanded collagenous materials can be used to prepare a wide variety offistula plug devices. Methods for preparing such plug devices caninclude contacting an ECM or other collagenous starting material with analkaline substance in an amount effective to expand the material,casting or otherwise forming the expanded collagenous material into aplug shape (e.g. one of those described herein), and lyophilizing theexpanded material to form a dried plug device.

Medical graft products of the invention may include biocompatiblematerials derived from a number of biological polymers, which can benaturally occurring or the product of in vitro fermentation, recombinantgenetic engineering, and the like. Purified biological polymers can beappropriately formed into a substrate by techniques such as weaving,knitting, casting, molding, and extrusion. Suitable biological polymersinclude, without limitation, collagen, elastin, keratin, gelatin,polyamino acids, polysaccharides (e.g., cellulose and starch) andcopolymers thereof.

Suitable biocompatible medical products of the invention can alsoinclude a variety of synthetic polymeric materials including but notlimited to bioresorbable and/or non-bioresorbable plastics.Bioresorbable, or bioabsorbable polymers that may be used include, butare not limited to, poly(L-lactic acid), polycaprolactone,poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolicacid-co-trimethylene carbonate), polyhydroxyalkanaates,polyphosphoester, polyphosphoester urethane, poly(amino acids),cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate),copoly(ether-esters) (e.g., PEO/PLA), polyalkylene oxalates, andpolyphosphazenes. These or other bioresorbable materials may be used,for example, where only a temporary blocking or closure function isdesired, and/or in combination with non-bioresorbable materials whereonly a temporary participation by the bioresorbable material is desired.

Non-bioresorbable, or biostable polymers that may be used include, butare not limited to, polytetrafluoroethylene (PTFE) (including expandedPTFE), polyethylene terephthalate (PET), polyurethanes, silicones, andpolyesters and other polymers such as, but not limited to, polyolefins,polyisobutylene and ethylene-alphaolefin copolymers; acrylic polymersand copolymers, vinyl halide polymers and copolymers, such as polyvinylchloride; polyvinyl ethers, such as polyvinyl methyl ether;polyvinylidene halides, such as polyvinylidene fluoride andpolyvinylidene chloride; polyacrylonitrile, polyvinyl ketones; polyvinylaromatics, such as polystyrene, polyvinyl esters, such as polyvinylacetate; copolymers of vinyl monomers with each other and olefins, suchas ethylene-methyl methacrylate copolymers, acrylonitrile-styrenecopolymers, ABS resins, and ethylene-vinyl acetate copolymers;polyamides, such as Nylon 66 and polycaprolactam; alkyd resins,polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxy resins,polyurethanes; rayon; and rayon-triacetate. For further informationconcerning suitable synthetic materials (both biodegradable andnonbiodegradable), useful in certain embodiments of the presentinvention, reference can be made, for example, to U.S. Utility PatentApplication Pub. No. 2005/022848 6 titled, “Implantable Frame withVariable Compliance,” filed on Apr. 11, 2005 (“Express Mail” MailingLabel No. EV 327 135 804 US), which claims priority to U.S. ProvisionalPatent Application titled, “Implantable Frame with Variable Compliance,”filed on Apr. 13, 2004. Such synthetic materials can be used to formfistula plug devices as described herein, either alone or in combinationwith ECM or other collagenous materials herein identified.

Turning now to a discussion of particular medical graft products,systems, and methods of the present invention useful for treatingfistulae, illustrative medical graft products of the invention areconfigured to block at least the primary opening of a fistula, i.e., theprimary opening and potentially one or more other segments of a fistula,for example, the fistula tract and/or any secondary openings. In thiscontext, the term “fistula tract” is meant to include, but is notlimited to, a void in soft tissues extending from a primary fistulaopening, whether blind-ending or leading to one or more secondaryfistula openings, for example, to include what are generally describedas simple and complex fistulae. Fistula grafts of the invention includea biocompatible graft body including a capping member and an elongateplug member extending from the capping member. The capping member isconfigured to contact portions of the alimentary canal wall adjacent tothe primary opening, and the elongate plug member is configured toextend into at least a portion of the fistula tract. In performing thesefunctions, the capping member and the elongate plug member can exhibitany suitable size and shape and can include any suitable device and/ormaterial, as long as the graft body is able to block at least theprimary opening of a fistula.

In some embodiments, the present invention provides fistula graftproducts that are useful in treating gastrointestinal fistulae.Illustratively, these products can be configured to block at least afistula opening occurring in an alimentary canal wall, and particularlythose occurring in the stomach and intestine. In advantageousembodiments, these products will at least include a capping member andan elongate plug member extending from the capping member, wherein thecapping member is configured to contact portions of the alimentary canalwall adjacent to the fistula opening, and the elongate plug member isconfigured to extend into, and in some cases fill, at least a portion ofa gastrointestinal fistula tract. While these products are particularlysuited for treating gastrointestinal fistulae, it will be understoodthat such products may be useful in treating other types of fistulae aswell, and in some forms, are useful in filling, blocking or otherwisetreating non-fistula openings or passages occurring in the body.

Any capping member present in an inventive product may be constructedalong with the elongate plug member to provide a single unitaryconstruct, for example, a single-capped device formed from a singlepiece of material or other substance. In some embodiments, a particularcapping member may be formed separately from and an elongate plug memberand then subsequently combined or otherwise retained in association withthe plug member, for example, by suturing the two together, applying anadhesive, using mechanical fastener(s), or employing any other suitablemeans or combination thereof. In one embodiment, an inventive medicalgraft product comprises an elongate plug member and a capping member,wherein the capping member is formed separately from the plug member andis hingedly coupled to an end of the plug member, e.g., before or duringan implantation procedure. In certain aspects, a capping member and anelongate plug member are formed from separate pieces of material, yetare retained in association with one another without the use of anotherdevice or material (e.g., sutures, an adhesive, etc.). In such aspects,the elongate plug member and one or more capping members are joinedtogether by having at least one member (or any portion thereof) receivedaround, through, over, etc., at least one other member (or any portionthereof).

In some forms, one or more capping members are each formed separatelyfrom an elongate plug member, and then coupled to the plug member withan absorbable device or material. These coupling elements can exhibitany suitable size, shape, and configuration, and in some embodiments,take the form of an adhesive or one or more hooks, fasteners, barbs,straps, suture strands, or combinations thereof. Additionally, suchdevices and materials can be configured to degrade at varying rates uponbeing implanted in vivo. In one embodiment, 2-0 vicryl suture materialis used to join one or more capping members to an elongate plug member.Illustratively, a coupling element can be adapted to desirably hold oneor more capping members in association with a plug member during producthandling and implantation, and then upon implantation, to degrade at adesirable rate. In some modes of operation, a capping member and anelongate plug member, at least due in part to degradation of thecoupling element, can uncouple or otherwise disengage from one anotherafter a period of time following implantation, allowing the cappingmember to pass through and out of the body naturally. In certainembodiments, the capping member can be hingedly coupled to the elongateplug member. By “hingedly coupled” is meant that the capping member isnot rigidly fixed to the elongate body member and can therefore tilt orswing relative to the elongate body member while still being coupled toit. For example, prior to loading the medical graft product into adeployment device such as a sheath (e.g., Flexor® sheath available fromCook Urological, Inc., 1100 West Morgan Street, P.O. Box 227 Spencer,Ind. 47460) the capping member can be tilted a distance toward anopposing end (i.e., from the distal end towards the proximal end or viceversa) of the elongate body member and rolled over the elongate bodymember so as to allow for the medical graft product to be positionedinto a deployment device. In this respect, the capping member has animplantable configuration wherein the opposite sides of the member arebrought in closer proximity to one another so as to be able to fitwithin the lumen of a delivery device, such as a catheter or sheath. Incertain aspects, the distal end of the deployment device can be insertedinto a fistula, for example, into a secondary opening, through a fistulatract, and a distance out of the primary opening. Thereafter, the graftbody (or at least the capping member) can be delivered from thedeployment device, allowing the capping member to expand. Then, thegraft body can be pulled back through the fistula tract until thecapping member contacts portions of the alimentary canal wall adjacentto the primary opening. The delivery device can then be withdrawn fromthe fistula through the secondary opening while maintaining the positionof the graft body with a pusher rod or any other suitable means, leavingthe graft deployed within the fistula and blocking at least the primaryfistula opening.

The capping member is configured to contact portions of the alimentarycanal wall adjacent to the primary opening. The capping member mayinclude a frame comprising a single piece of superelastic wire or othermaterial having a plurality of sides and bends interconnecting adjacentsides. The bends can be coils, fillets, or other configurations toreduce stress and fatigue. The single piece of wire is preferably joinedby an attachment mechanism, such as a piece of cannula and solder, toform a closed circumference frame.

The frame can comprise a metallic material including but not limited tostainless steel, titanium, cobalt, tantalum, gold, platinum, nickel,iron, copper and the like, as well as alloys of these metals (e.g.,cobalt alloys, such as Elgiloy®, a cobalt-chromium-nickel alloy, MP35N,a nickel-cobalt-chromium-molybdenum alloy, and Nitinol®, anickel-titanium alloy). Additionally or alternatively, suitable framescan include material in the form of yarns, fibers, and/or resins, e.g.,monofilament yarns, high tenacity polyester, and the like. A frameelement can also include other plastic, resin, polymer, woven, andfabric surgical materials, other conventional synthetic surgicalmaterials, such as a shape-memory plastic, and/or combinations of suchmaterials. Further, appropriate ceramics can be used, including, withoutlimitation, hydroxyapatite, alumina and pyrolytic carbon. Such metallicand other materials may be used in forming other expandable andnon-expandable graft body components useful in the present invention. Acapping member can also include a flexible material covering extendingbetween sides of the frame. Such a covering can be formed with anysuitable material such as but not limited to DACRON®, THORALON®, PTFE,collagen, submucosa, or other flexible material, and can be attached tothe frame with sutures or other suitable attachment means.

The capping member can be comprised of a frame in the form of a tulipfilter. The capping member may also include a flexible material coveringattached to the tulip filter frame. Such a covering can be formed withany suitable material such as but not limited to DACRON, PTFE, collagen,submucosa, or other flexible material, and can be attached to the tulipfilter with sutures or other suitable means. In certain other aspects,such a covering is not included as part of the capping member.

The components of an inventive graft construct (e.g., an elongate plugmember and a capping member), whether formed separately or together as asingle unit, can be constructed in any suitable manner, for example,using any of the processes described herein. In some embodiments, anelongate plug member and a capping member are formed with areconstituted or otherwise processed ECM material. Elongate plug membersand capping members can also be formed by folding or rolling, orotherwise overlaying one or more portions of a biocompatible material,such as a biocompatible sheet material. The overlaid biocompatible sheetmaterial can be compressed and dried or otherwise bonded into avolumetric shape such that a substantially unitary construct is formed.In some forms, an inventive graft component such as the elongate graftbody is constructed by randomly or regularly packing one or more piecesof single or multilayer ECM sheet material within a mold and thereafterprocessing the packed material. Elongate plug members useful in theinvention can be prepared, for example, as described in InternationalPatent Application Serial No. PCT/US2006/16748, filed Apr. 29, 2006, andentitled “VOLUMETRIC GRAFTS FOR TREATMENT OF FISTULAE AND RELATEDMETHODS AND SYSTEMS” (Cook Biotech Incorporated), which is herebyincorporated by reference in its entirety.

When formed separately, a capping member may or may not be comprised ofthe same biocompatible material(s) as the elongate plug member (or, ifpresent, another capping member). In certain aspects, the elongate plugmember and/or any capping member present are comprised of a remodelablematerial, and in some cases a remodelable collagenous material.Illustratively, a capping member and an elongate plug member can beformed from separate pieces of remodelable, collagenous material (e.g.,remodelable SIS material), and thereafter coupled to one another inaccordance with the present invention. In certain embodiments, theelongate plug member can be formed of lyophilized ECM material, and thecapping member can be formed of a stiffer ECM material, such as anair-dried or vacuum pressed ECM material. In advantageous embodiments,the capping member can be formed of a vacuum pressed, multi-laminate ECMconstruct, for example having from about two to about ten ECM layersbonded to one another.

As well, inventive graft products and their components can exhibit anysuitable size and shape for treating gastrointestinal fistulae and otherbodily openings and passageways. An elongate plug member may either havea constant or varying cross-sectional area along its length. Forexample, elongate plug members useful in the invention may exhibit agenerally cylindrical shape, a conical shape, a shape having tapered andnon-tapered longitudinal portions, or other suitable shapes havingrectilinear and/or curvilinear portions. Also, as discussed in moredetail below, some elongate graft bodies of the invention can have oneor more lumens extending at least partially through the bodies alongtheir length. A capping member can include one or more objects (e.g.,pieces of material) that, together or alone, exhibit a three-dimensionalrectilinear or curvilinear shape. Suitable three-dimensional rectilinearshapes can have any suitable number of sides, and can include, forexample, cubes, cuboids, tetrahedrons, prisms, pyramids, wedges, andvariations thereof. Suitable three-dimensional curvilinear bodies caninclude, for example, spheres, spheroids, ellipsoids, cylinders, cones,and any suitable variations thereof (e.g., a segment of a sphere, or atruncated cone, etc.). Capping members useful in the invention can beprepared, for example, as described in International Patent ApplicationSerial No. PCT/US2007/061371, filed Jan. 31, 2007, and entitled “FISTULAGRAFTS AND RELATED METHODS AND SYSTEMS FOR TREATING FISTULAE” (CookBiotech Incorporated), which is hereby incorporated by reference in itsentirety.

Illustrative elongate plug members of the invention will be ofsufficient size and shape to extend into at least a portion of a fistulatract, and will generally (but not necessarily) be of sufficientdimension to fill a fistula, or a segment thereof, e.g., the primaryfistula opening, a fistula tract, and/or any secondary fistula openings,either alone or in combination with other similar or differing devices.In certain embodiments, the elongate plug member will have a length ofat least about 0.20 cm, and in many situations at least about 1 cm toabout 20 cm (approximately 1 to 8 inches). In illustrative embodiments,the plug member will have a length of from about 2 cm to about 5 cm, oralternatively, from about 2 inches to about 4 inches. Additionally, incertain embodiments, elongate plug members will have a diameter, whichmay or may not be constant along their length, of from about 0.1 mm toabout 25 mm, or more typically from about 5 mm to about 10 mm. Incertain embodiments, a generally conical plug member is tapered alongits length so that the end of the plug member proximate the cappingmember has a diameter of about 5 mm to about 10 mm and the opposite endof the plug member has a diameter of about 0.5 mm to about 3 mm. Such ataper may or may not be continuous along the length of the elongate plugmember.

The elongate plug member may comprise a compliant sheet formbiocompatible material comprising two or more layers of ECM materialbonded together. This sheet form elongate plug member can be coupled toor otherwise joined with any of the capping members described herein,for example, the capping member of FIG. 1. This sheet form plug membercan be prepared, for example, as described in International PatentApplication Serial No. PCT/US2006/16233, filed Apr. 29, 2006, andentitled “FISTULA GRAFT WITH DEFORMABLE SHEET-FORM MATERIAL” (CookBiotech Incorporated), which is hereby incorporated by reference in itsentirety.

The sheet form material is deformable upon impingement by soft tissuesurrounding a fistula (e.g., tissue surrounding the primary fistulaopening, the fistula tract, and/or any secondary fistula openings)and/or upon impingement by walls of the lumen of a delivery device. Suchdeformable materials can include any of the ECM or other biocompatiblematerials described herein, for example, a multilaminate sheet ofremodelable SIS material. Further, the sheet form plug is sized andshaped so as to be deformable to a three-dimensional volumetric bodyextending into at least a portion of the fistula tract, and potentiallyfilling at least a portion of the fistula tract, the primary opening,and/or any secondary openings of the fistula. In so doing, advantageousimplant materials will also be sufficiently flaccid to avoid substantialcutting or tearing of the surrounding soft tissues.

In certain aspects, a sheet form graft body is shaped and sized suchthat the diameter of the primary opening is less than the width of thesheet so that the sheet of material as deployed in the fistula tract isfolded and/or rolled over itself one or more times to conform to softtissues surrounding the fistula and lodge within the fistula tract. Suchlodging in place may be sufficient to obviate the need for otherwisesecuring the graft to the soft tissues at or near the primary opening,fistula tract, and/or any secondary openings. Nonetheless, in certainaspects, the graft is further secured to such soft tissues, for example,by suturing.

Inventive graft body formation methods can involve manipulating graftmaterial within a mold or form. It should be noted that the graftmaterial may or may not be hydrated when placed in, on, around, etc. amold or form. In some methods, a substantially dry ECM material (e.g., apowder or sheet material) can be placed in a mold and then suitablyhydrated for further processing. In other methods, a hydrated startingmaterial is placed in and/or on a mold or forming structure for furtherprocessing. For example, one or more hydrated sheets of ECM material canbe applied to a form, e.g., wrapped at least partially around a mandrelso that portions of the sheet(s) overlap. Then, the one or more sheetscan be dried, and in some embodiments, dried while under compression, toform a unitary graft construct. In some modes of operation, a hydratedgraft material is provided within a single- or multiple-part mold havinga plurality of apertures or holes extending through a wall of the mold,thereby providing access to the mold interior from an external location.These apertures can serve to enhance drying of a hydrated materialduring a processing step and in processes exerting vacuum pressure atthese apertures, can promote and/or facilitate formation of surfaceprotuberances on the graft material as portions of the same are drawntoward the apertures while under vacuum. In one aspect, an amount of ECMmaterial is retained in such a mold, and needles or othermaterial-displacing objects are inserted through some or all of the moldapertures and a distance into the ECM material, thereby displacingvolumes of the ECM material. This can be performed when the graftmaterial is hydrated, partially hydrated or dehydrated. In some forms,with needles inserted in a hydrated ECM material and providing passagestherein, the material is subjected to conditions (e.g., freezing and/ordehydrating conditions) which, alone or in combination with one or moreother conditions, cause or allow the passages to be generally retainedin the ECM material after the needles are removed.

In one embodiment, one or more sheets of hydrated ECM material aresuitably wrapped and/or randomly packed around a mandrel, and then amold having a plurality of holes extending through a wall of the mold isplaced around the material-covered mandrel, for example, so that anamount of pressure is placed on the ECM material. The mandrel can thenoptionally be removed. Thereafter, needles or other material-displacingobjects are inserted through some or all of the holes and at leastpartially through the ECM material, thereby displacing volumes of theECM material. The ECM material is then at least partially dried. In someaspects, a suitable lyophilization technique is employed, e.g., one withor without a pre-freezing step as described herein. In these or otherdrying methods in which needles or other penetrating elements are to beleft within the mass during drying, these elements can optionally beprovided with a plurality of apertures or holes or can otherwise besufficiently porous to facilitate the drying operation by allowing thepassage of hydrate from the wet mass. In one embodiment, a hydrated ECMmaterial with emplaced needles can be subjected to freezing conditionsso that the material and any contained hydrate become substantiallyfrozen. Thereafter, the needles can be removed from the ECM material,and the remaining construct (with the frozen material passagessubstantially retaining their shape) can be placed under a vacuum sothat the frozen hydrant sublimes from the material, thereby resulting ina dry graft construct with retained passages therein.

In other modes of operation, passage-forming structures can beincorporated integrally into a mold so that passageways are formed uponintroducing the starting material in and/or on the mold. In theseaspects, the passage-forming structures can be part of the mold (e.g.,extend from a surface of the mold), or they can be separate objectsattached or otherwise coupled to the mold, to provide the desiredpassage or passages through the ultimately-formed graft body.

Although not necessary to broader aspects of the invention, in someaspects, the formation of such a graft construct comprises wrapping oneor more sheets of hydrated graft material around a mandrel a number oftimes. The resulting roll of graft material is then introduced into amold, and the mandrel is removed (optional), e.g., before or afterapplying the mold. Thereafter, multiple material-displacing objects suchas but not limited to needles are forced through apertures in the moldand into the hydrated graft material, and the material is subjected toone or more drying techniques such as a lyophilization process. In otheraspects, the formation of such a graft construct includes placing aflowable graft material into a mold and then subjecting the graftmaterial to further processing. For example, a flowable ECM materialmass, such as a gel, paste or putty, potentially incorporating aparticulate ECM material, can be placed into a mold, and then withvolumes of material displaced in the mass (e.g., by penetratingneedles), the ECM material can be dried or otherwise caused to form anintegral piece to provide a graft body having passages therein.Illustratively, each of the passages can be provided by forcing a singleobject through the material mass, or alternatively, where a mandrel isleft in place to form a longitudinal lumen, by forcing two objects intothe mass and toward one another from opposite directions until they abutthe mandrel. The mass can then be processed to a solid graft body asdiscussed herein.

When implanted in accordance with the present invention, and thuscontacting portions of the alimentary canal wall adjacent to the primaryopening, the capping member may or may not have a portion extending intothe primary opening. For example, in some aspects, the graft body isconfigured so that no portion of the capping member resides within theprimary opening when the graft body is implanted, while in otheraspects, the graft body is configured so that a portion of the cappingmember does reside within the primary opening when the graft body isimplanted. Also, it should again be noted that the graft body as awhole, i.e., the combination of the capping member and the elongate plugmember, is configured to block at least the primary opening of afistula. However, neither the capping member portion of the graft bodynor the elongate plug member portion of the graft body need beconfigured to block the primary fistula opening independent of the othermember, although either member may be so configured. Additionally, thecapping member portion of the graft body, by itself, may or may not beconfigured to block the fistula tract. In this regard, blocking aparticular space or void can be accomplished by filling that space withthe capping member, or a portion thereof. In certain aspects, thecapping member can be configured to fill the primary opening and/or aportion of the fistula tract. Such filling can, in some embodiments,seal off or substantially seal off the primary opening and/or a portionof the fistula tract.

When suitably implanted, and thus extending into at least a portion ofthe fistula tract, the elongate plug member may or may not have aportion extending into the primary opening. For example, in someaspects, the graft body is configured so that at least a portion of theelongate plug member resides within the fistula tract but no portion ofthe elongate plug member resides within the primary opening when thegraft is implanted. In other aspects, the elongate plug member isconfigured to extend through the primary opening and into at least aportion of the fistula tract when the graft body is implanted. Again, incertain embodiments it is the graft body as a whole, i.e., thecombination of the capping member and the elongate plug member, that isconfigured to block at least the primary opening of a fistula. Neitherthe capping member portion of the graft body nor the elongate plugmember portion of the graft body need be configured to block the primaryopening independent of the other member, although either member may beso configured. Additionally, the elongate plug member portion of thegraft body, by itself, may or may not be configured to block the fistulatract. Further, the elongate plug member portion, by itself, may or maynot be configured to block any secondary fistula opening. In thisregard, blocking a particular space or void can be accomplished byfilling that space with the elongate plug member, or a portion thereof.In certain aspects, the elongate plug member can be configured to fillthe primary opening, the fistula tract (or any portion thereof), and/orany secondary openings of the fistula. Such filling can, in someembodiments, seal off or substantially seal off the primary opening, thefistula tract (or any portion thereof), and/or any secondary opening ofthe fistula.

In certain aspects, the medical graft product comprises a materialreceptive to tissue ingrowth. In such aspects, upon deployment of theproduct in accordance with the present invention, cells from the patientcan infiltrate the material, leading to, for example, new tissue growthon, around, and/or within the medical graft product. In someembodiments, the medical graft product comprises a remodelable material.In these embodiments, the remodelable material promotes and/orfacilitates the formation of new tissue, and is capable of being brokendown and replaced by new tissue in such a way that the original fistulaclosure achieved by the implanted graft product is maintained throughoutthe remodeling process so as to eventually form a closure or substantialclosure with the new tissue.

Remodelable ECM materials having a relatively more open matrix structure(i.e., higher porosity) are capable of exhibiting different materialproperties than those having a relatively more closed or collapsedmatrix structure. For example, an ECM material having a relatively moreopen matrix structure is generally softer and more readily compliant toan implant site than one having a relatively more closed matrixstructure. Also, the rate and amount of tissue growth in and/or around aremodelable material can be influenced by a number of factors, includingthe amount of open space available in the material's matrix structurefor the infusion and support of a patient's tissue-forming components,such as fibroblasts. Therefore, a more open matrix structure can providefor quicker, and potentially more, growth of patient tissue in and/oraround the remodelable material, which in turn, can lead to quickerremodeling of the material by patient tissue.

In this regard, any component of a medical graft product of theinvention (including any ECM material) can have a level or degree ofporosity. In certain embodiments, the porosity of a layer of ECMmaterial is lowered by drying the material under compression. Ingeneral, compressing a pliable open matrix material, such as a pliableECM material, increases the material's bulk density and decreases thematerial's porosity by decreasing the size of the voids in the openmatrix. As is the case in certain aspects of the invention, when such amaterial is dried while being compressed, particularly under vacuumpressing conditions, the open matrix structure can become somewhat fixedin this relatively higher bulk density, lower porosity state (i.e., in arelatively more collapsed state). It should be noted that differentcompressing and drying techniques and/or methods, including differentdegrees of compressing and drying, can be designed through routineexperimentation so as to allow for a material layer having an optimaldegree of material bulk density and/or porosity for a particularapplication or procedure.

In certain aspects, a medical graft product of the invention includes atleast two regions exhibiting differing properties, e.g., differingporosities. Such differing regions can be established in certainlocations, for example, locations providing a particular arrangement orpattern on and/or within the medical product, and in some forms, suchdiffering regions are formed by subjecting the medical product to asuitable differential drying process. Illustratively, a graft body canbe configured so that the capping member occupies a more diminishedporosity region, while the elongate plug member occupies a more openporosity region. In this configuration, the diminished matrix region canhelp isolate the fistula tract from the alimentary canal, thusinhibiting bacteria and other undesirable substances from passing intothe alimentary canal from the fistula, while the more open matrix regionserves to promote more rapid closure of the fistula with its desirableremodeling properties.

While the present invention may be embodied in many different forms, forthe purpose of promoting an understanding of the principles of thepresent invention, reference will now be made to the embodimentsillustrated in the drawings, and specific language will be used todescribe the same. It will nevertheless be understood that no limitationof the scope of the invention is thereby intended. Any alterations andfurther modifications in the described embodiments and any furtherapplications of the principles of the present invention as describedherein are contemplated as would normally occur to one skilled in theart to which the invention relates.

With reference now to FIGS. 1A-1D, shown are perspective views of anillustrative medical graft product 10 of the present invention. Morespecifically, FIG. 1A represents the medical graft product 10 itsoriginal configuration, FIG. 1B represents the medical graft product 10in an intermediate configuration, FIG. 1C represents the medical graftproduct 10 in its implantable configuration, and FIG. 1D illustrates themedical graft product 10 in its implantable configuration being insertedinto a deployment device 17. The medical graft product 10 includes abiocompatible graft body 11 that is configured to block at least theprimary opening of a fistula. The graft body 11 includes a cappingmember 12 and an elongate plug member 13, which extends from the cappingmember 12. The elongate plug member 13 includes a proximal end 15 and adistal end 16. The capping member 12, which is formed with an ECMmaterial (e.g., SIS), is generally in the shape of a disk and isconfigured to contact portions of the alimentary canal wall adjacent tothe primary opening, particularly those openings occurring within thestomach and/or intestines. The elongate plug member 13, which is alsoformed with an ECM material, is generally in the shape of a cylinder andis configured to extend into at least a portion of the fistula tract.The capping member 12 is hingedly coupled to the distal end 16 of theelongate plug member 13 by suture 14. It should be noted that theelongate plug member 13 (and any other plug member described herein) mayor may not be sized and shaped to fill an entire fistula tract.

With regard to the intermediate configuration, FIG. 1B illustrates themedical graft product depicted in FIG. 1A where the capping member 12 isswung over the elongate plug member 13 from distal end 16 towardsproximal end 15. This process is made possible by the hinged coupling ofthe capping member 12 to the distal end 16 of the elongate plug member13. Typically, the capping member 12 will be loosely coupled to theelongate plug member such that the capping member 12 can be easilyfolded over the elongate plug member by a practitioner or during amanufacturing process. Once positioned at least partially overlappingplug member 13, the capping member 12 can be rolled or wrapped aroundthe elongate plug member 13 as shown in FIG. 1C to arrive at theimplantable configuration. In the implantable configuration shown,device 10 includes a portion of the capping member 12 conformed aroundplug member 13 and a leading portion of capping member 12 extendingdistally beyond the distal end of plug member 13. Other configurationsin which at least a portion of the capping member 12 is conformed to theouter surface of plug member 13 can also be used. Once in itsimplantable configuration, the medical graft product 10 can be insertedinto deployment device 17 and can be implanted within a patient so thatcapping member 12 contacts portions of alimentary canal wall adjacent toa primary opening, and the elongate plug member 13 extends into at leasta portion of fistula tract. To facilitate visualization duringdeployment, deployment device 17 can have a radiopaque band 18 or othermarker positioned at its distal end. In this manner, fluoroscopicimaging can be used to track the position of the distal end of deliverydevice 17, for instance to identify the point at which such distal endhas entered the alimentary canal. Once the medical graft product isdelivered, the capping member can regain its original shape or otherwiseexpand and thus contact portions of an alimentary canal wall adjacent tothe primary opening of a fistula when graft 11 is pulled proximally.

An alternative graft embodiment 10′ is depicted in FIG. 1E. This graftdevice is similar to that depicted in FIGS. 1A-1D, except that it alsoincludes a suture material or another tether 19′ passed through acentral lumen 20′ and attached to the capping member. This tether canprovide means for adjusting the position of the device during and/orafter deployment, and potentially also provide means for anchoring thedevice, for example, by suturing device 10′ to patient tissue at oradjacent to a fistula opening. In one mode of use, after deployment ofgraft 10′ from the lumen of a delivery device as discussed above, tether19′ can be used to pull graft device 10′ in a proximal direction tolodge capping member 12′ against the wall of the alimentary canal. Forthese purposes, it will be understood that other modes of attachment oftether 19′ to any suitable location of graft device 10′ could be used,so long as they enable repositioning the graft device 10′ by pulling onthe tether 19′.

In another form, a graft device having a lumen such as that depicted inFIG. 1E, the lumen also extending through capping member 12′, can bedelivered over the wire in order to treat the fistula. Such a graftdevice can have tether 19′ or can optionally lack the tether 19′.Delivery over the wire can be facilitated using a cannulated pusher toforce the graft device 10′ along the wire, e.g. starting from thefistula opening in the skin and continuing until the capping member 12′enters the alimentary canal and expands, generally as discussed above.In such embodiments, the presence of a tether attached at some point tothe device 10′ (e.g. to the capping member as depicted or at or near theproximal end of device 10′ opposite the capping member) can provide ameans by which the device 10′ can then be pulled proximally to lodgecapping member 12′ against the canal wall.

In certain forms of the invention, a graft product incorporates ananchoring adaptation to maintain the capping member in contact withportions of the alimentary canal wall adjacent the primary openingfollowing product implantation. For example, the medical graft productof the invention can include an adhesive for maintaining this type ofcontact. Adhesive can be applied to the graft product before animplantation procedure, e.g., during manufacture of the product, oralternatively, can be applied to the graft product and/or to tissue ator near the primary opening during such an implantation procedure. Othersuitable anchoring adaptations include but are not limited to barbs,hooks, sutures, protuberances, ribs, and the like. Again, such anchoringadaptations, while advantageous in certain forms of the invention, arenot necessary to broader aspects of the invention. Illustratively,certain medical graft products are configured so that the capping memberis able to maintain contact with portions of the alimentary canal walladjacent to the primary opening following implantation without the needfor such anchoring adaptations. In other aspects, suitable anchoringadaptations aid or facilitate the maintenance of such contact. Inembodiments where the capping member is constructed so as to fit withina deployment device, such as the one depicted in FIGS. 1A-1D, suchanchoring adaptations will be selected so as not to interfere with thisprocess (i.e., the anchoring adaptations, if any, will not obstruct themedical graft product from being easily loaded and deployed from saiddeployment device).

In certain aspects, the invention provides biocompatible graft bodiesthat include an expandable element (e.g., an expandable material and/ordevice). In this regard, inventive graft bodies may be provided, whereinthe capping member, the elongate plug member, or both have the capacityto expand. For example, the capping member and/or the elongate plugmember can include, for example, a suitable ECM foam or sponge formmaterial.

Illustratively, a graft body, or any portion thereof, may comprise aporous, three-dimensionally stable body formed with one or more suitablebiocompatible matrix materials. Such biocompatible matrix materials caninclude naturally-occurring polymers and/or synthetic polymers. Morepreferred sponge compositions will comprise collagen as a matrix-formingmaterial, either alone or in combination with one or more other matrixforming materials, and particularly preferred sponge compositions willcomprise an ECM material such as those discussed elsewhere herein. Ingeneral, sponge matrices useful in certain embodiments of the presentinvention can be formed by providing a liquid solution or suspension ofa matrix-forming material, and causing the material to form a porousthree-dimensionally stable structure; however, a sponge or foam materialcan be formed using any suitable formation method, as is known in theart. For additional information concerning foam or sponge form materialsthat can be useful in certain embodiments of the present invention,reference can be made, for example, to U.S. Pat. App. Pub. No.2003/0013989.

In some forms, a compact, stabilized sponge construct used to form theelongate graft body and/or capping member is highly expansive whenwetted, which can desirably enhance the ability of the graft body toblock (and to continue blocking) at least the primary opening of afistula. In illustrative procedures, a suitable hydrant, such as saline,may be applied or delivered to the graft body after it is suitablylocated within a patient to enhance the expansion of the body within thefistula tract and/or a fistula opening. Alternatively, or additionally,a bodily fluid of the patient can sufficiently wet the implanted graftbody so as to promote the expansion of the body within the fistula.

These compact, stabilized sponge constructs and other expandable graftbody elements, when used in the invention, can allow the graft body toattain a more low-profile configuration during a deployment step. Forexample, an illustrative deployment system can include a graft body,wherein the capping member (and optionally also the elongate plugmember) is comprised of an expandable device and/or material such thatin a stabilized, compressed first configuration, the graft body can fitwithin an end of a delivery device (e.g., a probing device, deliverysheath, or other similar instrument), which is sized and configured totraverse a fistula tract. Illustratively, this end of the deliverydevice can be passed into a secondary opening, through a fistula tract,and out of a primary opening into the alimentary canal. Thereafter, thegraft body (or at least the capping member portion of the graft body)can be pushed or otherwise removed from the delivery device in asuitable manner to allow the capping member to attain an expanded secondconfiguration. In such an expanded configuration, the capping member,which was previously able to traverse the primary fistula opening, isnow sized and shaped to contact portions of the alimentary canal walladjacent the primary opening so that at least a portion of the cappingmember cannot pass back through the primary opening.

Additionally, in illustrative embodiments, one or more anchors, barbs,ribs, protuberances, and/or other suitable surface modifications can beincorporated on and/or within an illustrative graft body to roughen,condition, or otherwise deepithelialize at least a portion of thefistula, such as the fistula tract and/or the primary opening, duringand/or after emplacement of the graft within the tract. The conditioningof the tract tissue can serve to initiate a localized healing responsein patient tissue that can be advantageous in enhancing the ingrowth ofpatient tissue into an illustrative plug construct, such as a plugcomprising an ECM material. Further, in illustrative embodiments, wherea suture, leader, or string is used to assist with the emplacement of anillustrative graft construct within a tract, as is discussed elsewhereherein, the leader can comprise an abrasive material, or comprise one ormore sections and/or surface features and/or adaptations, e.g. one ormore bristles that can directionally emanate from the leader materialand that can serve to roughen or otherwise condition or de-epithelializepatient tissue upon travel through and/or location within a fistulatract.

In certain aspects, medical graft products of the invention incorporatean adhesive or, where appropriate, a sclerosing agent to facilitateand/or promote blocking of at least the primary opening of the fistula.As well, fistula treatment methods of the invention can include stepswhere such substances or materials are applied to a medical graftproduct being deployed and/or to the soft tissues surrounding thefistula. For example, an adhesive, glue or other bonding agent may alsobe used in achieving a bond between a medical graft product of theinvention and the soft tissues defining a fistula opening or tractand/or adjacent tissues. Suitable bonding agents may include, forexample, fibrin or collagen gels or pastes, gelatin, or other agentsincluding reactive monomers or polymers, e.g., cyanoacrylate adhesives.In some forms of the invention, a fistula treatment method includescontacting soft tissue surfaces surrounding the fistula, e.g., softtissue surfaces at or near the primary opening and/or soft tissueslining the fistula tract, with a sclerosing agent prior to forcing thesheet from material into the fistula. Such use of a sclerosing agent candeepithelialize or otherwise damage or disrupt these soft tissuesurfaces, leading to the initiation of a healing response.

A plurality of passages formed or otherwise occurring in a graft bodymay be present in any suitable number in an inventive product. Thesepassages can exhibit a variety of shapes and sizes, and can extendthrough all or a portion of the body. In some forms, one or morepassages extend from a graft body surface and includes a generallycoherent passage wall. Illustratively, a tubular graft body having aninternal lumen extending through the body along its length can havepassages extending partially or entirely through a wall of the tube,e.g., from an exterior surface to an interior surface of the tube wall.Also, the spacing and size of a passage in a graft body relative toanother passage in the body, as well as the depth to which a particularpassage extends into a graft body, can vary. In some forms, the passagesare generally cylindrical voids, e.g., having diameters ranging fromabout 0.05 mm to about 15 mm, more typically from about 0.10 mm to about5 mm, and even more typically from about 0.1 mm to about 1.0 mm. Theseand other graft body passages useful in the present invention can bespaced any suitable distance from one another, and in some embodiments,are positioned in a particular pattern (e.g., in rows), although aplurality of passages can be randomly placed as well. Further, aplurality of passages in a construct can be configured so that any onepassage extends the same or a different distance into the constructrelative to any other passage in the construct.

Further in this regard, passages occurring in a graft body may be formedin any suitable manner. In some embodiments, passages can be created ina graft body after the graft body is formed, e.g., after a castcollagenous material is dried to form a coherent body. In someembodiments, at least part of the formation of some or all of thepassages in a graft body occurs during formation of the graft body.Illustratively, an inventive method can include a step where a passageis initially provided in a hydrated material mass, e.g., by displacing avolume of material in the mass. Then, with the passages present in thehydrated material mass, the mass can be subjected to suitable dryingconditions (e.g., a lyophilization step) to cause or allow the passagesto be retained in the dried graft body. It should be noted that ahydrated material in such processes (e.g., a reconstituted ornaturally-derived collagenous material) can have a level of hydrationincluding full or partial hydration, and in this regard, a dryingprocess can be used to lower starting material hydration to any suitablelevel including substantially dehydrated. Also, displacing a volume ofmaterial in a hydrated mass of material to create a passage can beaccomplished in a variety of manners, and in certain aspects, involvesforcing or otherwise introducing an implement or othermaterial-displacing object (e.g., a cannulated or non-cannulated needle)into the mass. Other suitable material-displacing objects can beselected according to the type of passage desired.

Turning now to a general discussion regarding methods of the inventionfor treating fistulae, suitable treatment methods include providing amedical graft product such as any of those described above, andimplanting the product within a patient so that: (i) the graft bodyblocks at least the primary opening of a fistula, i.e., the primaryopening and potentially one or more other segments of a fistula, forexample, the fistula tract and/or any secondary openings; (ii) thecapping member contacts portions of the alimentary canal wall adjacentto the primary opening; and (iii) the elongate plug member extends intoat least a portion of the fistula tract. In some modes of operation, thedistal end of a deployment device can be inserted into a fistula, forexample, into a secondary opening, through a fistula tract, and adistance out of the primary opening. Thereafter, the graft body (or atleast the capping member) can be removed from the device, for examplewith a push rod or other suitable device, allowing the capping member toexpand or to at least retain its original shape prior to loading of thegraft body into the deployment device. Then, the graft body can bepulled back through the fistula tract until the capping member contactsportions of the alimentary canal wall adjacent to the primary opening.The delivery device can then be withdrawn from the fistula through thesecondary opening, leaving the deformed sheet-form material deployedwithin at least a portion of the fistula tract, and potentially fillingat least a portion of the fistula tract, the primary opening, and/or anysecondary openings of the fistula.

Products and methods of the invention can be used to treat any fistula,and in particular embodiments, fistulae having a primary opening in awall of the alimentary canal, such as those occurring in the stomach orintestine. In some aspects, the invention provides medical graftproducts and methods useful for blocking openings anywhere on or withinthe body of a patient, for example, blocking at least the primaryopening of a urethro-vaginal fistulae, vesico-vaginal fistulae,tracheoesophageal fistulae, gastrointestinal fistulae, and any number ofanorectal fistulae, such as recto-vaginal fistula, recto-vesicalfistulae, recto-urethral fistulae, or recto-prostatic fistulae. Inpreferred embodiments, the medical graft products of the invention aredesigned to treat a gastrointestinal fistula, such as an enterocutaneousfistula. Also, inventive products and methods can be used to treat afistula regardless of its size and shape, and in some forms, areutilized to treat a fistula having a primary opening, secondary opening,and/or fistula tract with a diameter ranging from about 1 millimeter toabout 20 millimeters, more typically from about 5 millimeters to about10 millimeters.

Medical products of the invention can be implanted using any suitabledelivery method or placement technique. Illustratively, a graft body canbe implanted by pulling or pushing the graft body into a suitableposition within a fistula. For example, the elongate plug member end ofthe body can be pulled toward a secondary opening within the fistulatract (e.g., through the primary opening and into the fistula tract)until the capping member contacts portions of the alimentary canal walladjacent to the primary opening. In certain embodiments, such pullingcan be accomplished using a fistula probe or other suitable instrument,for example, an appropriately configured pair of surgical hemostats thatinclude a portion passable into a secondary opening, through the fistulatract, and potentially out of the primary opening. Thereafter, theelongate plug member portion of the graft body can be releasably graspedby the probe or otherwise coupled to the probe and pulled into theprimary opening. In other embodiments, an illustrative graft body issuitably deployed using a biocompatible sheath or catheter, which can beconfigured to traverse the tract of a fistula, and is optionally locatedwithin the fistula tract over a suitable wire guide or under endoscopicguidance. In these embodiments, an illustrative graft construct can bedeployed in an over-the-wire configuration or through an unobstructedsheath lumen. In addition to those described elsewhere herein, suitabledelivery devices and systems useful in such embodiments of the inventioncan be prepared and used, for example, as described in InternationalPatent Application Serial No. PCT/US2007/061380, filed Jan. 31, 2007,and entitled “FISTULA GRAFT DEPLOYMENT SYSTEMS AND METHODS” (CookBiotech Incorporated), which is hereby incorporated by reference in itsentirety.

Fistula treatment methods of the invention may include an endoscopicvisualization (fistuloscopy) step. Such endoscopic visualization can beused, for example, to determine the shape and size of the fistula, whichin turn can be used to select an appropriately sized and shaped medicalgraft product for treating the fistula. Illustratively, a very thinflexible endoscope can be inserted into a secondary opening of thefistula and advanced under direct vision through the fistula tract andout through the primary opening. By performing fistuloscopy of thefistula, the primary opening can be accurately identified. Also,cleaning of the fistula can be performed prior to and/or duringdeployment of a medical graft product of the invention. For example, anirrigating fluid can be used to remove any inflammatory or necrotictissue located within the fistula prior to engrafting the product. Incertain embodiments, one or more antibiotics are applied to the medicalgraft product and/or the soft tissues surrounding the fistula as anextra precaution or means of treating any residual infection within thefistula.

The present invention also provides, in certain aspects, medicalproducts that include a radiopaque element such as but not limited to aradiopaque coating, attached radiopaque object, or integrated radiopaquesubstance. In this regard, the capping member and/or elongate plugmember of some inventive graft bodies may be comprised of a radiopaqueelement so that, for example, the movement of the product may bemonitored and the product may be placed at a desired location. Anysuitable radiopaque substance, including but not limited to, tantalumsuch as tantalum powder, can be incorporated into a medical product ofthe invention. Other radiopaque materials comprise bismuth, iodine, andbarium, as well as other suitable markers.

The capping members described herein can be shaped and configured in avariety of manners. In some instances, a capping member includes aresilient wire frame or other similar frame or frame-like supportdevice. These devices can, in some embodiments, be designed to movebetween a first device configuration and a second device configuration,for example, in the case of a frame that is compactable to a compacted,first condition, and when in this compacted condition, is thenexpandable to an expanded, second condition. In forms where a frame hasthe capacity to expand, these frames can include those that areself-expanding and those that require at least some manipulation inorder to expand. In certain embodiments, an inventive support frame isunable to freely fit inside a delivery device lumen when in a firstcondition (e.g., in a generally relaxed state), but then can bemanipulated into a second condition for placement in the lumen. In thelumen, the frame is constrained by interior device surfaces that definethe lumen. Upon removal from the lumen, the frame then generally returnsto the first condition.

With reference now to FIG. 2A, shown is a support frame 40 which can beincorporated into a grafting device of the invention. Support frames ofthis sort and other similar devices useful in the present invention canbe constructed using one or more pieces of stainless steel wire, superelastic wire or any of a variety of other suitable materials describedherein or otherwise known to those skilled in the art. In thisparticular embodiment, support frame 40 includes a single piece ofNitinol wire having a plurality of sides and bends interconnectingadjacent sides. Bends of this sort can include coils, fillets, or othersuitable configurations, for example, those designed to reduce stressand fatigue. Support frame 40 incorporates optional bend adaptations 41having apertures occurring therein as generally shown. The single pieceof wire is preferably connected to itself by an attachment mechanism,such as a piece of cannula and solder, to form a closed circumferenceframe. In some aspects, a closed circumference frame (e.g., an octagonalframe) rather than being constructed by joining together parts of one ormore other objects (e.g., ends of a single piece of wire) is insteadformed as a closed circumference frame, for example, as a unitary devicein a mold or form, or developed from a larger piece of material (e.g.,laser cut from a metallic sheet of material). While a preferred frameembodiment is an eight-sided polygon such as that shown in FIG. 2A,other shapes having rectilinear and/or curvilinear components arecontemplated as well, for example, circular or oval shapes or otherpolygonal shapes having three, four, five, six, seven or any suitablenumber of sides.

Support frame 40, which is shown in a relaxed condition in FIG. 2A, is aresilient device. Thus, the frame can be deformed (e.g., collapsed,compressed, etc.) from this relaxed, first condition to a deformed,second condition. In this deformed, second condition, the resilientframe is then poised to essentially return to its relaxed, firstcondition. Illustratively, support frame 40 can be compressed into acompressed condition (e.g., by folding one or more times and/or rollingportions of the frame) for positioning in a delivery device lumen havinga relatively smaller diameter than that which the frame could otherwisefit in its relaxed condition. In this compressed condition, the framethen has the ability to self-expand essentially back to its prior,relaxed condition upon being removed from the delivery device lumen.

In a preferred embodiment, a capping member includes a support frame anda deformable covering material. The support frame and covering materialcan each be formed with one or more of a variety of materials.Illustratively, a support frame formed with a resilient material (e.g.,Nitinol) can be combined with a sheet-form resorbable or non-resorbablematerial, and in some cases, a multilayered (e.g., remodelable)material, wherein this combination provides a suitable arrangement forblocking, and in some cases sealing off, a fistula opening. Arrangementsof this sort include but are not limited to capping members that includea support frame that can lie in a single, generally flat plane, and asheet-form deformable covering material extending between peripheralregions of the support frame, although a variety of other capping membershapes and configurations are contemplated as within the scope of thepresent invention. Some of these devices can be used to treat fistulaehaving a primary opening in a bowel wall, and in this regard, may beeffective to block or otherwise exclude the bowel lumen from the fistulatract when desirably deployed. Covering materials can be manipulatedbefore, during and/or after being combined with a support member. Insome cases, a covering material will be already-formed before beingassociated with a support frame. In other cases, a covering materialwill be fully or partially formed in the presence of a support frame orportion thereof. When present, a covering material that is to becombined with a support device can be attached to or otherwise suitablyassociated with the support device in a variety of manners includingsome that involve bonding and/or mechanically fastening the coveringmaterial to the device. In some cases, an edge of a covering material isfolded over a frame segment and attached to another portion of thematerial to provide a sleeve or other channel-like adaptation forretaining the covering material in association with the support frame.

Certain embodiments of the invention provide capping members includingan expandable or otherwise deformable frame member associated with afull or partial covering of material on one or more surfaces of (e.g.,an inner and/or outer surface) of the expandable frame member. In someembodiments, the covering material is associated in a unique manner withthe expandable frame member. For example, the covering material may becontoured snugly around or completely or partially embed elements of theexpandable frame member to assist in maintaining the attachment of thecovering material to the expandable frame member. This may avoid,reduce, or simplify the need for other mechanical attachments, such assutures, to hold the covering material to the expandable frame member.It may also in some forms provide a unique, relatively fixed associationof the covering material with the expandable frame member or elementsthereof, even during contraction and/or expansion of the frame.Illustratively, coverings that completely or partially embed a framemember can be made by casting a polymerizable, crosslinkable orotherwise hardenable flowable material onto and around all or a portionof the frame member, and then causing the flowable material topolymerize, crosslink and/or otherwise harden. In some other cases, aflexible material can be positioned around a frame, and then thematerial physically, chemically and/or otherwise altered (e.g., vialyophilization, heating, etc.) so that the material becomes lessflexible for maintaining the material in association with the frame.

Capping member support frames, when used in the present invention, canbe associated with one or more of a variety of materials to formeffective capping arrangements. Useful covering and other materials forcapping purposes include naturally-derived and non-naturally-derivedmaterials such as those described elsewhere herein. Both resorbable andnon-resorbable materials may be employed in this regard. In somepreferred embodiments, polymeric materials are associated with supportstructures to form useful capping members. These include synthetic andnon-synthetic polymers. These various materials can be applied to orotherwise associated with support members in a variety of mannersincluding some that involve mechanical fastening of an already-formedmaterial, forming material along and/or around portions of the frame(e.g., in a mold or form, by spray coating, dip coating, etc.),thermoforming, solvent dissolution, and variations and combinationsthereof.

In some cases, a flexible covering material that is pulled taught alonga collapsible support frame can fold and/or roll along with a frame asit collapses, and upon the frame returning to its prior shape, can alsoessentially return to its prior condition to again be pulled taught.Referring now to FIG. 2B, shown is a capping member 50 that incorporatesthe support frame from FIG. 2A. Capping member 50 additionally includesa deformable covering material 52 attached to and extending betweenopposing, peripheral edges of the frame. In a preferred embodiment,capping member 50 will generally be sized and configured so that whenpositioned over a fistula opening in a bodily structure wall (e.g., aprimary fistula opening in an alimentary canal wall), outer regions ofthe capping member (i.e., those including the support frame) extendbeyond the opening along the bodily structure wall and contact portionsof the bodily structure wall adjacent to the opening, and inner regionsof the capping member cover and block the opening.

In some cases, a capping member such as capping member 50 will includeat least one elongate device (e.g., a suture, plug member, etc.)extending therefrom. For example, an elongate plug can be connected to(e.g., sutured, glued, etc.) covering material 52 such as in a region ofthe material that is centrally located relative to the support frameperimeter. In this manner, the device can be positioned in a patientsuch that capping member 50 is positioned over a fistula opening, andthe elongate plug member extends into a fistula tract extending fromthis opening. In this position, the elongate plug member can be pulledaway from the capped fistula opening such that portions of deformablecovering material 52 are drawn into the fistula tract. Desirably,support frame 40 provides an anchor of sorts for capping member 50 sothat as inner regions of covering material 52 are drawn into the fistulatract, support frame 40 and outer regions of covering material 52 remainoutside of the fistula tract. In some cases, when a sufficientlyflexible covering material is pulled in this manner, portions of thecovering material can deform to provide a convex or other similarsurface for contacting patient tissue at the fistula opening to seal orsubstantially seal off the opening.

FIGS. 3A and 3B show a medical graft device 60 of the present inventionthat includes a capping member 70 and a generally cylindrical, elongateplug member 72 extending from this capping member. Plug member 72 isconfigured to extend into and fill at least a portion of a fistulatract, and its dimensions including its length can vary, with thoseskilled in the art recognizing suitable plug dimensions for a particularapplication. In some cases, a plug length is provided for extendingthrough an entire fistula tract up to about 15 cm or longer, althoughsuch a plug could be cut to size as desired to fit all or a portion of aparticular tract. As well, elongate plug member 72 can be formed withone or more of a variety of materials, and in some preferredembodiments, is formed with a rolled sheet-form material such as but notlimited to a single- or multi-layered naturally-derived material (e.g.,a collagenous ECM material). Capping member 70, which includes adeformable covering material 73, is similar to that shown in FIG. 2Bexcept that it additionally includes a sheath portion 74 extending away(in a generally perpendicular direction) from a centrally-located regionof its bottom surface. Capping member 70 includes a top surface 76.Sheath portion 74 is configured to be positioned over and extend alongat least a segment of plug member 72 as generally shown in FIG. 3A. Aplurality of sutures 78 attach sheath portion 74 to plug member 72,although a variety of other attachments means are contemplated as withinthe scope of the present invention.

A capping member sheath portion useful in the invention can be formedseparately from, and then subsequently united with, the remainder of acapping member, or alternatively, can be formed as part of an existingcapping member component. In this particular embodiment, sheath portion74 comprises a portion of covering material 72 extending away from theremainder of the capping member. Illustratively, a sheath portion ofthis sort can be formed by providing a covering material sufficientlysized to be wrapped around a support frame with enough material leftover on one side to form a sheath or sheath-like capping membercomponent. In some cases, a somewhat flexible material is positionedaround a frame in such a manner, and then the material is physically,chemically and/or otherwise treated (e.g., lyophilized, heated, etc.) sothat the material becomes less flexible for maintaining the material inthe desired configuration.

Referring again to FIG. 3B, in some modes of use, graft device 60 isimplanted within a patient such that capping member 70 is positionedover a fistula opening 80 occurring in a bodily structure wall 90, andelongate plug member 72 extends into a fistula tract 91 extending fromthis opening. In this position, plug member 72 can be pulled in thedirection of the arrow shown (i.e., away from the capped fistulaopening) such that portions of deformable covering material 73 are drawninto the fistula tract as generally shown. In an alternative embodiment,graft device 60 incorporates a tether extending from elongate plugmember 72 (e.g., away from the end opposite capping member 70), whichmay be useful in manipulating the position the device at certain pointsduring delivery. A tether of this sort may be a suture (e.g., a 2-0vicryl suture) embedded within, attached to or otherwise associated withplug member 72.

Desirably, the support frame will be sized and configured so that itremains outside of the fistula tract (e.g., along the bodily structurewall in an area extending a suitable distance beyond the fistulaopening) even when a considerable amount of pulling force is applied toplug member 72. In this manner, when capping member 70 is deformed asshown in FIG. 3B, the support frame and an externally remaining portion100 of the covering material will remain outside of the fistula tract,while a portion of the covering material that previously (i.e., prior todeformation) resided outside of the fistula tract will now reside withinthe fistula tract to provide an internalized covering material portion101. In some forms, the capping member is deformed so that portions ofthe covering material very snugly conform to patient tissue at thefistula opening in a generally non-planar condition such as a cupping orcup-like arrangement. The plug member 72 can then be secured inposition, e.g., using one or more sutures to patient tissue, to retainthe conforming condition of the capping member.

Graft device 60 and other similar inventive devices are particularlysuitable for treating enterocutaneous and other gastrointestinalfistulae, although such devices can be adapted to treat a variety ofother fistulae as well. These devices can be implanted in any suitablemanner. In a preferred embodiment, graft device 60 is placed with theaid of a delivery sheath or other similar delivery device, for example,a splittable sheath as discussed in more detail below. In one mode ofoperation, the distal end of a wire guide is passed into anenterocutaneous fistula tract through a secondary fistula opening andtoward a primary fistula opening under fluoroscopic guidance. The wireis advanced until its distal end enters the alimentary canal through theprimary opening. Thereafter, the distal end of an over-the-wiredilator-sheath combination is advanced through the tract in a similarmanner, for example, until the sheath is positioned at or just beyondthe primary opening. The dilator is then removed, leaving the sheath(e.g., a check-flow sheath) and potentially also the guidewire in thetract. In some cases, the wire guide is removed with the dilator. Then,a suitably sized and shaped graft device such as graft device 60 isloaded into the sheath through its proximal end, for example, with thecapping member 70 in a compressed condition (e.g., folded one or moretimes and/or rolled) entering the sheath first, and elongate plug member72 following. The plug member may then be fully pushed into the sheathby hand. The capping member, in a compressed condition, is poised toreturn to its expanded condition upon being removed from the deliverydevice lumen.

Next, an over-the-wire pusher is introduced into the sheath proximal endand advanced toward the sheath distal end until at least a portion ofthe graft device is desirably pushed from the sheath distal end (e.g.,with capping member 70 in an expanded condition and extending a distanceinto the alimentary canal). In some cases, the capping member and/orplug member will incorporate a device or material to aid in imaging thedevice during delivery. Illustratively, a stainless steel button orother similar device may be attached to the end of the plug member nearthe capping member. As well, a capping member support frame can beformed with a radiopaque material. Alternatively, a support frame can beformed with a resorbable material such as a collagenous ECM material(e.g., SIS), polycaprolactone, polyhydroxyalkanoates- or PHA polymers,etc. with a radiopaque marker attached.

Then, the pusher can be placed in contact with the plug member 72 toprovide back pressure, while the delivery sheath is removed, thusmaintaining desirable positioning of the device inside the tract. Afterthe sheath and pusher are removed, plug member 72 can be manipulated toachieve a desired deformation of capping member 70, for example, asdescribed above. With capping member 70 desirably deformed, plug member72 can then be secured in place (e.g., sutured or otherwise fixed topatient tissue at and/or around the secondary fistula opening) tomaintain the capping member in this deformed condition. In some cases,the plug member will extend a distance out of the secondary opening whenthe capping member is deformed. This portion may optionally be trimmedoff before or after the plug is secured in place. Although not necessaryto broader aspects of the present invention, in the current embodiment,plug member 72 is directly or indirectly attached to the underside ofthe material defining the capping member top surface 76, and in thisregard, internalized covering material portion 101 includes some of thematerial defining this surface. In one aspect, a support frame isattached to a covering material with resorbable sutures, allowing theframe to separate from the remainder of the graft device after a certainamount of time following initial plug deployment, and pass through andout of the alimentary canal.

In some preferred embodiments, care is taken to not block or otherwiseclose the secondary opening to facilitate drainage of the tractfollowing the implantation procedure, for example, during remodelingwhen a remodelable material is utilized in the plugging assembly. Ofcourse, it will be understood that the steps described above can occurin any suitable order as will be recognized by those skilled in the art.For example, a graft device may be preloaded into a delivery devicebefore the delivery device is positioned in a fistula tract. In somecases, when a delivery system component (e.g., a wire guide, dilator,pusher, etc.) is deemed not necessary for a particular deliveryapplication, this component will be excluded from the delivery systemand any associated methods of delivery.

FIG. 4A shows a medical graft device 120 according to another embodimentof the present invention. Device 120 includes a capping member 121 andan elongate plug member 122 extending from the capping member. Plugmember 122 is configured to extend into and potentially fill a fistulatract. Such a plug member may be formed as described elsewhere herein,for example, as described in regard to the plug member depicted in FIGS.3A and 3B. In some cases, a plug of this sort will have a length rangingfrom about 10 cm to about 20 cm, more typically from about 15 cm toabout 18 cm.

Capping member 121 is comprised of a deformable material 123 havingportions extending between outer edges of an octagonal, resilientsupport frame 124. Support frame 124 is a closed circumference framemade of Nitinol. In some preferred embodiments, the deformable materialis comprised of a polymeric material, e.g., a synthetic polymericmaterial such as but not limited to polyurethane materials such asTHORALON®, thermoplastic silicones, etc. In some instances, anaturally-derived material such as an ECM or other naturally-derivedmaterial is additionally or alternatively included. Such materials maybe coated with other material(s), for example, a PCL-coated orPLGA-coated collagenous material (e.g., a coated SIS material). Suchmaterials may be fully or partially formed on and/or around a supportframe, or alternatively, may be provided as a separate component andthen suitably combined with the support frame. In a preferredembodiment, a synthetic polymer is desirably thermoformed around asupport frame to fully or partially embed parts of the support frame.

Capping member 121 includes a top surface 127, which is configured toface the bowel lumen when the device is desirably implanted within afistula. Deformable material 123 also provides a sheath portion 128extending away (in a generally perpendicular direction) from acentrally-located region of the bottom surface of the capping member.Sheath portion 128 is configured to be positioned over and extend alongat least a segment of plug member 122 as generally shown in FIG. 4A. Aplurality of sutures 129 attach sheath portion 128 to plug member 122,although a variety of other attachments means are contemplated as withinthe scope of the present invention. A stainless steel or other suitableradiopaque marker may be incorporated into a distal region of device120. A tether 130 (e.g., suture material) is attached to the plug bodynear its proximal end, and can extend proximally away from the plug bodyto potentially aid in product handling and/or delivery.

Device 120 can be delivered into a fistula tract in any suitable mannerincluding that described above in relation to FIGS. 3A and 3B. In oneembodiment, capping member 121 is positioned in a delivery lumen suchthat a first edge portion of capping member 121 is deflected toward theproximal end of plug member 122, while a second (opposite) edge portionof capping member 121 is deflected generally in the opposite direction(i.e., away from the proximal end of plug member 122). In such acondition, a portion of capping member 121 will overlap or otherwiseextend back over and potentially wrap and conform to an exterior,lateral surface of plug member 122, while another portion of cappingmember 121 will extend out in front of the distal end of plug member122, although other folding or compaction patterns could be used incertain embodiments. An example of how device 120 can be positioned in adelivery device lumen is depicted in FIG. 4B. So positioned, the cappingmember is poised to return to its generally non-deformed condition uponbeing removed from the lumen of delivery device 131.

In some forms, capping member portions, which would otherwise beessentially perpendicular to the longitudinal axis of the plug memberwhen the capping member is in a generally relaxed condition, can be madeto reside in a parallel (or closer to parallel) position relative tothis longitudinal axis. When positioned in a delivery device lumen,these capping member portions may be constrained by and/or conform tointerior walls of the delivery device defining the lumen. As well, anyportions of the capping member extending along exterior, lateralsurfaces of the plug member may at least somewhat conform to these plugmember surfaces.

Plug member 122 is generally cylindrical, with a substantial portion ofthe plug having a first diameter. Near its distal end, the plug tapersto a second, smaller diameter as shown. This smaller diameter distal endregion may be useful to receive or otherwise accommodate portions of thecapping member which might be folded back over the plug member whendevice 120 is loaded into a delivery sheath, potentially allowing use ofa reduced diameter delivery sheath. Such recesses or other similarspaces for receiving or otherwise accommodating at least part of acapping member residing along a plug member portion will be recognizedby those skilled in the art, and therefore, are encompassed by thepresent invention. Device 120 additionally includes a thin cover 133,which is somewhat snugly positioned over plug member 122. Cover 133 canbe formed with any suitable material (e.g., a synthetic polymer), andmay be useful to protect the device during product storage, handlingand/or delivery. Device 120 may be sterilized before and/or afterplacement in cover 133. In one mode of delivery, device 120 istransferred directly from cover 133 and into an emplaced catheter orother similar delivery device so that the plug body 122 does not have tobe directly touched by the physician during deployment.

Delivery devices useful in certain aspects of the present invention havea lumen communicating with a distal, open end. This “leading” distal endis configured to pass into passageways and other open spaces in thebody. Although not necessary to broader aspects of the invention, thisdistal end, or any portion thereof, may be particularly configured toenhance travel of the device through certain body passageways, forexample, including a tapered portion and/or having a dome-shaped orotherwise rounded tip. Accordingly, such devices can exhibit anysuitable size, shape and configuration for performing the functionsdescribed herein, while avoiding substantially cutting or tearingsurrounding soft tissues.

Where a delivery device is used to deliver a graft device into a fistulatract, such a device may have a length of about 2 inches to about 12inches, more typically about 3 inches to about 9 inches, and even moretypically about 4 to about 8 inches. Also, these devices may have anoutside diameter of about 0.3 mm to about 3.2 mm, or about 0.5 to about3.0 mm, or even about 1.0 mm to about 2.5 mm. In some preferred forms,the outside diameter of a delivery device will range from about 0.3 mmto about 10.0 mm, more typically from about 2.0 mm to about 7.0 mm.

In some embodiments, a delivery device is rigid or substantially rigid,and is configured to be generally straight, for example, for use intreating certain simple or straight fistulae. Alternatively, deliverydevices useful in the invention can be configured to include one or moreportions that are curvilinear, bent, or otherwise suitably shaped. Incertain aspects, the distal end of a delivery device is curved to adegree to allow for easier passage of the distal end through a complexfistula, e.g., a horseshoe fistula, and/or through the primary fistulaopening and into the alimentary canal. In some forms, a delivery deviceis composed of a malleable material such as but not limited to a wovenor spirally-configured metal or alloy material, or a plastic(hydrocarbon-based) material, which may be bent to the necessary angleor curvature, for example, to allow passage through a fistula tract. Theshape of such a delivery device may be adjusted at certain intervals ofthe procedure so as to allow the delivery device to pass further andfurther into the fistula tract, until the primary opening is identified.In some forms, the delivery device is generally straight in a relaxedcondition but can flex to adapt to contours during passage.

In this regard, delivery devices, when used in the invention, can beformed with one or more of a variety of materials. A particular materialmay be selected to take advantage of one or more of its properties suchas but not limited to its weight, durability, flexibility, etc. Forexample, a device may comprise a material having properties that allowthe device to traverse a body passageway without buckling or kinking orcausing unacceptable damage to soft tissues defining the passageway.Illustratively, the device, or selected portions thereof (e.g., thedistal end), can exhibit a degree of flexibility. In this regard, adelivery device, or any portion thereof, may be rigid, malleable,semi-flexible, or flexible. In certain embodiments, an endoluminallyadvanceable device is particularly adapted for moving through and intobody passages that angulate sharply or curve abruptly such as whentraversing the alimentary canal, passing through and into a fistulaopening, traversing a fistula tract, etc. In some of these embodiments,the device is configured to be directable or steerable through thepassageway, and therefore, exhibits desirable characteristics, e.g.,sufficient stiffness, to allow an operator to apply an adequate degreeof ante-grade force to the device to allow it to traverse a passagewayin a desirable manner.

Suitable materials for forming delivery devices or device components ofthe invention can include but are not limited to metallic materialsincluding stainless steel, titanium, cobalt, tantalum, gold, platinum,nickel, iron, copper and the like, as well as alloys of these metals(e.g., cobalt alloys, such as Elgiloy®, a cobaltchromium-nickel alloy,MP35N, a nickel-cobalt-chromium-molybdenum alloy, and Nitinol®, anickel-titanium alloy). Additionally or alternatively, the deliverydevice can include material in the form of yarns, fibers, and/or resins,e.g., monofilament yarns, high tenacity polyester, and the like. Adelivery device can also include other plastic, resin, polymer, woven,and fabric surgical materials, other conventional synthetic surgicalmaterials, such as a shape-memory plastic, and/or combinations of suchmaterials. Further, appropriate ceramics can be used, including, withoutlimitation, hydroxyapatite, alumina and pyrolytic carbon.

In some forms, a flexible delivery device will incorporate one or moreadaptations for facilitating removal of the device from the body duringa delivery procedure. Illustratively, a protective sleeve canincorporate scores, thinner portions, and other openings andnon-openings that weaken a portion of the sleeve to facilitate asplitting operation in removing the sleeve from the tract. Such aweakened portion may include any suitable means for facilitating tearingor breaking along the area. In certain beneficial forms, a protectivesleeve is controllably separable longitudinally into two or more piecesfor removal, for example, as occurs in Peel-Away® catheters availablefrom Cook Incorporated, Bloomington, Ind., USA. Such an apparatus with aseparable sleeve is particularly useful in treating fistulae that have asecondary opening in the outer skin surface and a primary opening thatis relatively difficult to access other than through the fistula tract,e.g. as occurs in a large percentage of enterocutaneous fistulae. In oneaspect, a delivery system comprises a suitably sized and configuredinner dilator, a splittable sheath, and a “pusher” device that istranslatable through the sheath, wherein all of these can be receivedover an emplaced guidewire.

In some forms, an inventive device incorporates at least one object thatcan be X-ray, sonographically, or otherwise non-invasively visualized todetermine its location in the body. Some inventive grafting devices,deployment systems, etc. are equipped with at least two imageablecomponents such that the relative positioning of these components in thebody can be verified during and/or after a procedure. These types ofconfigurations are particularly useful in devices and systems havingimageable components that can be caused or allowed to move relative toone another in the body such that the relative movement of thecomponents can be tracked and verified during delivery, deployment, etc.Various device designs are contemplated in this regard. When a device orsystem includes multiple visualizable objects, any two of these objectsmay or may not be connected to one another. In some instances, a deviceis configured such that a particular arrangement of imageable componentscan be visualized from outside the body to indicate successfuldeployment, anchoring, function of the device, etc. Illustratively, whenviewed from a particular vantage point outside the body, desirablepositioning of two device components inside the body may be confirmed bymeasuring the distance between the two components as viewed from thisvantage point. In other forms, two imageable components may be spacedfrom one another initially when viewed from a particular vantage pointoutside the body, and desirable positioning of the components inside thebody may be confirmed by visualizing one component eclipsing the othercomponent, for example, as viewed from this vantage point. Suitablemarkers and other imageable objects include those made from stainlesssteel, tantalum, platinum, gold, or other suitable materials. As well,substances containing tantalum, barium, iodine, or bismuth (e.g. inpowder form) can be applied to inventive devices for imaging purposes.

With reference now to FIG. 5, shown is a capping member 150 according toanother embodiment of the invention. Capping member 150 includes agenerally octagonal, resilient support frame 151 embedded within adeformable covering material 152. An embedded frame arrangement of thissort can be provided in a variety of manners as described elsewhereherein, for example, by casting apolymerizable, crosslinkable orotherwise hardenable flowable material onto and around all or a portionof the frame member, and then causing the flowable material topolymerize, crosslink and/or otherwise harden. In one preferredembodiment, an embedded arrangement is provided by positioning a closedcircumference wire frame between layers of a deformable material andthen bonding the layers together to at least partially embed the framein the material. In some cases, pieces of a somewhat flexible materialare positioned around a frame, and then the material is physically,chemically and/or otherwise treated (e.g., lyophilized, heated, etc.) sothat the material becomes less flexible and/or more uniform formaintaining the material in a desired configuration. In some forms, aNitinol frame is positioned between layers of a polyurethane materialsuch as THORALON® or a thermoplastic silicone, and then the layers areheated to thermoform the layers together around the frame. Yet, it willbe understood that support frame 151 and covering material 152 can eachbe formed with a variety of materials as described elsewhere herein, andthat the frame may be attached or otherwise associated with the coveringmaterial in other ways.

In this specific illustrative embodiment, capping member 150additionally includes a washer 153 having a center hole 154. Washer 153is positioned to the interior of support frame 151, and is also embeddedwithin covering material 152 although the washer can be associated withthe covering material in other non-embedded ways. Preferably but notnecessarily, washer 153 is formed with a material such as stainlesssteel that can be non-invasively visualized, thus making both washer 153and support frame 151 imageable in this way. While the relativedimensions of the various capping member components shown in FIG. 5 areadvantageous in certain embodiments of the invention, it will beunderstood that these dimensions can be varied as desired to suit aparticular application, patient, etc.

Covering material 152 may be desirably shaped (e.g., octagonally) andthen combined with the support frame, or alternatively relatively largepieces of material may be utilized initially and then trimmed to adesired shape once combined with the frame. In an illustrative mode offormation, a Nitinol wire support frame and a stainless steel washer arepositioned on a first, oversized sheet of polyurethane material.Thereafter, a second, oversized sheet of polyurethane material is placedover the first sheet in an overlapping relationship to sandwich thesupport frame and washer between the sheets. Any material layers used inthis regard may be of the same or different thickness. The overlappingmaterial layers are then pressed together (pressing optional) andthermoformed around the support frame and washer, thereby embeddingthese components between the thermoformed layers. Such a technique maybe effective to substantially seal these components in the material.Thereafter, a center hole can be made in the covering materialcorresponding to the center hole 154 in the washer, and excess amountsof material can be trimmed from the periphery of the covering material.If present, excess material can be trimmed so that there is little or nomaterial extending beyond the support frame. Alternatively, cappingmember 150 can be constructed such that covering material 152 includes aperipheral portion 155 extending a distance out and away from thesupport frame as shown.

In certain aspects of the invention, capping member 150 is combined withan elongate plug member to form a grafting device useful in the presentinvention. FIG. 6 shows a partial, side view of one illustrativeinventive device 158 which includes a generally cylindrical, elongateplug member 160 extending from capping member 150. Support frame 151 anddeformable covering material 152 are purposely not shown in FIG. 6 tomore clearly show washer 153 and its relationship to elongate plugmember 160 and other parts of the device. Plug member 160 has a distalend 161, and is configured to extend into and potentially fill a fistulatract. Its dimensions including its length can vary, with those skilledin the art recognizing suitable plug dimensions for a particularapplication. In some cases, a plug length is provided for extendingthrough an entire fistula tract up to about 15 cm or longer, althoughsuch a plug could be cut to size as desired to fit all or a portion of aparticular tract. As well, elongate plug member 160 can be formed withone or more of a variety of materials, and in some preferredembodiments, is formed with a rolled sheet-form material such as but notlimited to a single- or multi-layered naturally-derived material (e.g.,a collagenous ECM material). Illustratively, such a plug member may beformed as described elsewhere herein, for example, as described inregard to the plug member depicted in FIGS. 3A and 3B.

Capping member 150 and plug member 160 can be joined to one another inany suitable manner including some that involve bonding, suturing,coupling, mechanically fastening, etc. the two together. In someinstances, the two are coupled to one another with an absorbablecoupling device or material (e.g., an adhesive) to enable separation oruncoupling of the device components after a period of time followingimplantation, thus allowing the capping member to, for example, passthrough and out of the bowel with naturally occurring fecal matter whencertain fistulae are being treated. Such decoupling can be facilitatedand/or promoted by naturally occurring forces generated duringperistalsis. In certain forms, capping member 150 and plug member 160will be coupled together at least in part by filament, thread, suturematerial, etc. In the specific illustrative embodiment depicted in FIG.6, the two are held together with a system that includes a first,longitudinal pin 163 and a second, transverse pin 164. In a preferredembodiment, both of these pins are formed with PLGA or anotherabsorbable material. In some forms, suture material is substituted forone or both pins to provide a retaining member. For example, transversepin 164 can be replaced with 0 polydioxanone suture material thatattaches to longitudinal pin 163 to keep it seated in the plug.

Continuing with FIG. 6, capping member 150 can be positioned atop plugmember 160 such that washer 153 resides generally parallel to the plug'sdistal end 161. A central, longitudinal passage extends into plug 160from its distal end. Washer 153 can be generally centered over thedistal end of the plug so that the center hole 154 in the washer linesup with the opening to this longitudinal passage. A shank portion oflongitudinal pin 163 can then be inserted through the hole in washer 153and into the central, longitudinal passage in plug member 160.Longitudinal pin 163 has an enlarged head portion having a largerdiameter than hole 154, thereby allowing pin 163 to securely holdcapping member 150 atop plug member 160 when the pin is desirablyanchored in the plug. A lateral passage extends at least partiallythrough plug 160 near its distal end, and intersects with thelongitudinal passage in the plug. A shank portion of lateral pin 164 canbe inserted into this lateral passage and advanced until it desirablyengages longitudinal pin 163. The two pins, in some instances, can bemade to fit together (e.g., friction fit) or otherwise engage oneanother in a manner that desirably keeps the pins engaged to preventlongitudinal pin 163 from prematurely exiting plug 160.

FIGS. 8A and 8B show a retaining system according to one specificillustrative embodiment of the invention. This system can be employed asdescribed above in relation to FIG. 6, and includes a longitudinal pin200 and a lateral pin 201. Longitudinal pin 200 includes a shank portion202 extending from an enlarged head portion 203. A passage 204 extendsthrough shank portion 202 near the end of the shank opposite enlargedhead portion 203. Lateral pin 201 includes a shank portion 206 extendingfrom an enlarged head portion 207. Two protuberances 208 are positionedon each of opposite sides of shank portion 206. On each side, the twoprotuberance are spaced a distance from one another. When longitudinalpin 200 is positioned in a plug member as described above in relation toFIG. 6, the end of shank portion 206 opposite enlarged head portion 207can be inserted into the lateral passage in the plug member and intopassage 204 in the direction of the arrow shown. As shank portion 206 isadvanced, portions of shank portion 202 adjacent passage 204 willcontact the first, distal most protuberance on each side of shankportion 206. With sufficient force, shank portion 206 can be advanceduntil both distal protuberances pass entirely through passage 204 which,in some instances, may involve deformation of the protuberances. Whenboth distal protuberances pass entirely through passage 204, the widthof shank portion 202 will fit snugly in the space separating the twoprotuberances on each side of shank portion 206. Each protuberance willprovide a wall inhibiting shank portion 206 from backing out of passage204 and out of the plug. Also, shank portion 206 will preventlongitudinal pin 200 from backing out of the plug.

In addition to those shown, a variety of other alternatively shaped andconfigured protuberances, raised portions and other snap-fit typeadaptations may be utilized in the invention. As well, these types ofpins and other securing and retaining systems and their components canbe formed with one or more of a variety of biocompatible materialsincluding some that are resorbable and some that are nonresorbable. Inone preferred embodiment, such devices are constructed with PLGA oranother suitable resorbable material. Various other systems forattaching capping member 150 to plug member 160 will be recognized bythe skilled artisan and therefore are encompassed by the presentinvention. These include various single-and multiple-part devices suchas but not limited to those that deform to connect together, latchtogether, tie together, screw together, snap together, incorporate adetent mechanism, lock-fit together and variations and combinationsthereof. Additionally, any of these elements may be radiopaque orotherwise incorporate a radiopaque material for visualization purposesas discussed elsewhere herein, for example, for comparing thepositioning of one of these elements relative to a body part, otherdevice component, delivery member, etc. In some modes of use, graftdevice 158 is implanted within a patient such that capping member 150 ispositioned over a fistula opening 170 occurring in a bodily structurewall 171 (e.g., an intestinal wall), and elongate plug member 160extends into a fistula tract 172 extending from this opening. In thisposition and referring now to FIG. 7, plug member 160 can be pulled inthe direction of the arrow shown (i.e., away from the capped fistulaopening) such that washer 153 and portions of deformable coveringmaterial 152 are drawn into the fistula tract as generally shown.Portions of deformable covering material including peripheral portion155 remain outside the fistula tract. Peripheral portion 155 can, insome instances, promote and/or facilitate a better blockage or exclusionof the fistula tract from adjacent body lumens (e.g., the bowel lumen),and in some instances, will contribute to sealing off of a fistulaopening.

Continuing with FIG. 7, longitudinal pin 163 and lateral pin 164 arepurposely not shown in this illustration to more clearly show washer 153and deformable covering material 152 and their relationship to the otherdevice components and surrounding tissues. Graft device 158 mayoptionally incorporate a tether extending from elongate plug member 160(e.g., away from the end opposite capping member 150), which may beuseful in manipulating the position the device at certain points duringdelivery. A tether of this sort may be a suture (e.g., a 2-0 vicrylsuture, 0-PDS suture, etc.) embedded within, attached to or otherwiseassociated with plug member 160.

Desirably, support frame 151 will be sized and configured so that itremains outside of the fistula tract (e.g., along the bodily structurewall in an area extending a suitable distance beyond the fistulaopening) even when a considerable amount of pulling force is applied toplug member 160. In this manner, when capping member 150 is deformed asshown in FIG. 7, the support frame and an externally remaining portion175 of the covering material will remain outside of the fistula tract,while washer 153 and an internalized covering material portion 176 willnow reside within the fistula tract. Internalized covering materialportion 176 includes material that previously (i.e., prior todeformation) resided outside of the fistula tract. In some forms, thecapping member is made to deform so that portions of the coveringmaterial very snugly conform to patient tissue at the fistula opening ina generally non-planar condition such as a cupping or cup-likearrangement. As plug member 160 is pulled in the direction of the arrow,washer 153 moves away from support frame 151 in that same direction.Because support frame 151 and washer 153 are both formed withnon-invasively imageable materials, when viewed from a vantage pointcorresponding to, for example, that shown in FIG. 7, it is possible todetermine the relative positioning of the two components in the body asplug member 160 is pulled. This may be helpful, for example, todetermine when a desired amount of deformation of the capping member hasbeen achieved, for example, in an effort to try to seal off the fistulaopening in instances where such sealing off can be achieved. When it canbe visualized that the support frame and washer are desirably spaced oroff-set from one another, the plug member 160 then can be secured inposition, e.g., sutured to patient tissue using one or more sutures, toretain the conforming condition of the capping member. The desiredamount of off-set can vary depending perhaps on the materials ofconstruction of the grafting device, size of the fistula or other bodypassage being treated, etc.

Graft device 158 and other similar inventive devices are particularlysuitable for treating enterocutaneous and other gastrointestinalfistulae, although such devices can be adapted to treat a variety ofother fistula and non-fistula openings and other passages in the body.In some instances, these open spaces will occur naturally in the body,for example, as a native lumen or other open space in a bodily system,e.g., in an organ or other component of the circulatory, respiratory,digestive, urinary and reproductive, sensory, or endocrine systems. Incertain aspects, an opening to be treated is one that exists naturallyin the body but relates to a disease, defect, deformation, etc.Alternatively, an opening or passage to be treated may be one resultingfrom an intentional or unintentional trauma to the body including butnot limited to some relating to vehicular accidents, gunshots and othersimilar wounds, etc., as well as some formed by passage of a medicalinstrument (e.g., a needle, trocar, etc.) through cutaneous,subcutaneous, and/or intracutaneous tissue. In preferred embodiments,assemblies of the invention can be used to plug or otherwise fillfistulae such as but not limited to urethro-vaginal fistulae,vesico-vaginal fistulae, tracheoesophageal fistulae, gastro-cutaneousfistulae, and any number of anorectal fistulae, such as recto-vaginalfistula, recto-vesical fistulae, recto-urethral fistulae, orrecto-prostatic fistulae.

Inventive devices can be implanted in any suitable manner. In apreferred embodiment, graft device 158 is placed with the aid of adelivery sheath or other similar delivery device, for example, asplittable sheath as discussed elsewhere herein. In one mode ofoperation, the distal end of a wire guide is passed into anenterocutaneous fistula tract through a secondary fistula opening andtoward a primary fistula opening under fluoroscopic guidance. The wireis advanced until its distal end enters the alimentary canal through theprimary opening. Thereafter, the distal end of an over-the-wiredilator-sheath combination is advanced through the tract in a similarmanner, for example, until the sheath is positioned at or just beyondthe primary opening. The dilator is then removed, leaving the sheath(e.g., a check-flow sheath) and potentially also the guidewire in thetract. In some cases, the wire guide is removed with the dilator. Then,a suitably sized and shaped graft device such as graft device 158 isloaded into the sheath through its proximal end, for example, with thecapping member 150 in a compressed condition (e.g., folded one or moretimes and/or rolled) entering the sheath first, and elongate plug member160 following. The plug member may then be fully pushed into the sheathby hand. The capping member, in a compressed condition, is poised toreturn to its expanded condition upon being removed from the deliverydevice lumen.

Next, a pusher such as an over-the-wire pusher is introduced into thesheath proximal end and advanced toward the sheath distal end until atleast a portion of the graft device is desirably pushed from the sheathdistal end (e.g., with capping member 150 in an expanded condition andextending a distance into the alimentary canal). Then, the pusher can beplaced in contact with the plug member 160 to provide back pressure,while the delivery sheath is removed, thus maintaining desirablepositioning of the device inside the tract. After the sheath and pusherare removed, plug member 160 can be manipulated to achieve a desireddeformation of capping member 150, for example, as described above. Insome forms, it will be possible to grasp the plug body itself, forexample, by hand or with a suitable instrument, for manipulationpurposes. In other forms, the device will provide an extension (e.g., anattached suture) extending proximally from the plug body that can begrasped and manipulated. With capping member 150 desirably deformed(e.g., as verified by the imageable off-set distance between washer 153and support frame 151), plug member 160 can then be secured in place(e.g., sutured or otherwise fixed to patient tissue at and/or around thesecondary fistula opening) to maintain the capping member in thisdeformed condition. In some cases, the plug member will extend adistance out of the secondary opening when the capping member isdeformed. This portion may optionally be trimmed off before or after theplug is secured in place.

In some preferred embodiments, care is taken to not block or otherwiseclose the secondary opening to facilitate drainage of the tractfollowing the implantation procedure, for example, during remodelingwhen a remodelable material is utilized in the plugging assembly. Ofcourse, it will be understood that the steps described above can occurin any suitable order as will be recognized by those skilled in the art.For example, while not necessary to broader aspects of the invention, agraft device may be preloaded into a delivery device before the deliverydevice is positioned in a fistula tract. Illustratively, a graftingdevice may be housed in a sheath (e.g., Flexor® sheath) for storageand/or transport. Such a sheath may be perforated which may be useful tohydrate and/or sterilize the grafting device prior to deployment. Insome cases, when a delivery system component (e.g., a wire guide,dilator, pusher, etc.) is deemed not necessary for a particular deliveryapplication, this component will be excluded from the delivery systemand any associated methods of delivery.

In addition to graft device 158, the present invention provides a largevariety of devices and systems in which it will be useful to employmultiple visualizable objects. Implantable medical devices in certainaspects of the invention include a first imageable component, a secondimageable component and a device body that includes a deformable memberthat is deformable from a first condition to a second condition. Such adeformable member can be provided for anchoring, plugging, sealing,fixation, deployment, delivery and/or other purposes. The firstimageable component and the second imageable component are arranged suchthat upon deformation of the deformable member from the first conditionto the second condition, the position of the first imageable componentrelative to the second imageable component changes. Thus, in someembodiments, such a device is delivered to an implantation site in apatient. Thereafter, a deformable member (e.g., anchoring component) ofthe device is deformed from a first condition to a second condition suchthat the first imageable component changes position relative to thesecond imageable component. The change in position of the firstimageable component relative to the second imageable component can thenbe visualized, for example, to indicate when the device has beendesirably deployed. Devices in which it will be useful to incorporatemultiple visualizable objects include, for example, those described inInternational Patent Application Serial No. PCT/US2007/061371, filedJan. 31, 2007, and entitled “FISTULA GRAFTS AND RELATED METHODS ANDSYSTEMS FOR TREATING FISTULAE” (Cook Biotech Incorporated), and U.S.Provisional Patent Application Ser. No. 60/947,573, filed Jul. 2, 2007,both of which are hereby incorporated by reference in its entirety.

In some forms, a fistula is drained prior to receiving a medical graftproduct of the invention therein. Such draining can be accomplished byinserting a narrow diameter rubber drain known as a seton through thefistula. The seton is passed through the fistula tract and tied as aloop around the contained tissue and left for several weeks or months,prior to definitive closure or sealing of the fistula. This procedure isusually performed to drain infection from the area, and to mature thefistula tract prior to a definitive closure procedure.

In one embodiment, a medical graft product of the invention includes aleader in association with the graft body, for example, a suture gluedor tied to the graft body. This leader can be used to pull the graftbody into a suitable position within a fistula. In some aspects, afterthe leader is used to sufficiently locate a suitable fistula graftwithin a patient, the string can be removed from the graft, for example,using cutting shears. In alternative forms, the string or suture can bemade from a remodelable or otherwise absorbable material such that thestring or suture can be left in place within the fistula tract. In theseforms, the absorbable leader can be used to anchor or otherwise suitablysecure the fistula graft within the implantation site. For example, theleader can be tied to patient tissue at a suitable location, forexample, a location just inside or external to a secondary fistulaopening. Further, in alternative embodiments, an illustrative fistulagraft can be positioned so that it spans the entire length of a fistulatract, i.e., from the primary opening to a location at or external to asecondary opening. In these embodiments, the string or suture can beused to secure the tail of the graft to patient tissue at an externallocation.

Medical graft products of the invention can also be sealed withinsterile medical packaging. For example, a medical graft product can havepackaging including a backing layer and a front film layer. The medicalgraft product is sealed between the backing layer and the film layerutilizing a boundary of pressure-adhesive as is conventional in medicalpackaging. A cut-out may be provided in the backing layer to assist auser in separating the film layer from the backing layer.

Sterilization of a medical graft product may be achieved, for example,by irradiation, ethylene oxide gas, or any other suitable sterilizationtechnique, and the materials and other properties of the medicalpackaging will be selected accordingly. Also, medical graft products ofthe invention can be contained in sterile packaging in any suitablestate. Suitable states include, for example, a hydrated or dehydratedstate. The medical graft products can be dehydrated by any means knownin the art (e.g., lyophilization or air dried). If a medical graftproduct of the present invention is stored in a dehydrated state, it ispreferred that it retains all of its biological and mechanicalproperties (e.g., shape, density, flexibility, etc.) upon rehydration.

The materials and other properties of the packaging will be selectedaccordingly. For example, the package can include indicia to communicatethe contents of the package to a person and/or a machine, computer, orother electronic device. Such indicia may include the dimensions of, thetype of materials used to form, and/or the physical state of, thecontents of the package. In certain embodiments, a medical graft productis packaged for sale with instructions for use. For example, in aparticularly preferred embodiment, a medical product includes at leastone medical graft product sealed within a sterile package, wherein thepackaging has visible indicia identifying the at least one medical graftproduct as having physical characteristics as described herein, and/orcan contain or otherwise be associated with printed materialsidentifying the contents as having such physical characteristics andincluding information concerning its use as a medical graft product fortreating fistulae. The packaging can also include visible indiciarelating to the dimension of the at least medical graft product, and/orrelating to the treatment site(s) for which the at least one medicalgraft product is configured.

The present invention also provides a line of medical products, whereina medical product of the invention includes one or more medical graftproducts such as those described herein enclosed within a sealedpackage. When the medical product includes more than one medical graftproduct, for example, a plurality of medical graft products, theproducts can each be of substantially the same size and shape, or,alternatively, can vary with respect to size and shape.

Additionally, the medical graft products of the invention can bemodified before, during, and/or after deployment. Illustratively, aproduct may be cut, trimmed, sterilized, and/or treated (e.g., broughtinto contact, impregnated, coated, etc.) with one or more desirablecompositions, such as any of those previously disclosed herein, e.g.,anticoagulants (e.g., heparin), growth factors or other desirableproperty modifiers. In certain aspects, following deployment of a graftbody in accordance with the present invention, one or more portions ofthe body are trimmed off or otherwise removed, for example, materialprotruding from the primary opening and/or any secondary opening.

Further, the fistula treatment methods described herein can be used toclose one or more fistula during a given medical procedure. Also,methods of the invention can be used to treat complex fistula. Formultiple fistulae, multiple medical graft products can be engrafteduntil each of the fistula have been addressed. In cases of complexfistula, for example a horse-shoe fistula, there may be one primaryopening and two or more fistula tracts extending from that opening. Insuch instances, a medical graft product may be configured with a graftbody including one capping member and two or more elongate plug members.Each plug member can be drawn into the primary opening, and thereafterinto one of the fistula tracts extending therefrom. Each of the elongateplug members and/or the capping member of the body can be secured bysutures and/or an adhesive, if necessary, and any excess material can betrimmed. Still further, while discussions herein have focused upon thetreatment of fistulae, in certain embodiments, medical graft devices ofthe invention may be configured for and used in the treatment of otherundesired voids or tracts through body tissues caused by trauma, diseaseor other causes, particularly such voids or tracts that originate at anorgan wall or other tissue wall and extend into adjacent tissues.

The use of the terms “a” and an and the and similar referents in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. Recitation of ranges of values herein are merely intended toserve as a shorthand method of referring individually to each separatevalue falling within the range, unless otherwise indicated herein, andeach separate value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein, isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention unless otherwise claimed. Nolanguage in the specification should be construed as indicating anynon-claimed element as essential to the practice of the invention.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations of those preferred embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventors expect skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention tobe practiced otherwise than as specifically described herein.Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above-describedelements in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context. In addition, all patents and publications citedherein are indicative of the abilities of those of ordinary skill in theart and are hereby incorporated by reference in their entirety as ifindividually incorporated by reference and fully set forth.

LISTING OF CERTAIN EMBODIMENTS Embodiment 1

A method for implanting a medical device in a patient, comprising:

providing an implantable medical device, comprising:

-   -   a device body including a deformable anchoring component        deformable from a first condition to a second condition;    -   a first imageable component; and    -   a second imageable component;    -   delivering the device to an implantation site in the patient;

deforming the anchoring component from the first condition to the secondcondition, wherein the first imageable component changes positionrelative to the second imageable component; and

visualizing the change in position of the first imageable componentrelative to the second imageable component.

Embodiment 2

The method of embodiment 1, wherein the implantation site includes abodily passage.

Embodiment 3

The method of embodiment 1, wherein the implantation site includes anopening in a bodily passage wall.

Embodiment 4

The method of embodiment 3, wherein said deforming is effective to blockthe opening in the bodily passage wall.

Embodiment 5

The method of embodiment 3, wherein said deforming is effective tosubstantially seal off the opening in the bodily passage wall.

Embodiment 6

The method of embodiment 1, wherein the implantation site includes afistula opening in a bowel wall.

Embodiment 7

The method of embodiment 1, wherein the implantation site includes afistula tract.

Embodiment 8

The method of embodiment 1, wherein said visualizing includes X-rayvisualization.

Embodiment 9

An implantable medical device, comprising:

a device body including a deformable anchoring component deformable froma first condition to a second condition;

a first imageable component; and

a second imageable component,

wherein the first imageable component and the second imageable componentare arranged such that upon deformation of the anchoring component fromthe first condition to the second condition the position of the firstimageable component relative to the second imageable component changes.

Embodiment 10

The implantable medical device of embodiment 9, wherein the anchoringcomponent includes a resilient wire support frame.

Embodiment 11

The implantable medical device of embodiment 10, wherein the supportframe is formed with Nitinol.

Embodiment 12

The implantable medical device of embodiment 10, wherein the anchoringcomponent further includes a radiopaque component positioned to theinterior of the resilient wire support frame.

Embodiment 13

The implantable medical device of embodiment 9, wherein the device bodycomprises a synthetic polymeric material.

Embodiment 14

The implantable medical device of embodiment 9, wherein the device bodycomprises a collagen-containing material.

Embodiment 15

The implantable medical device of embodiment 9, wherein the device bodycomprises a remodelable material.

Embodiment 16

The implantable medical device of embodiment 9, wherein the device bodycomprises an extracellular matrix material.

Embodiment 17

The implantable medical device of embodiment 16, wherein saidextracellular matrix material comprises submucosa, serosa, pericardium,dura mater, peritoneum, or dermal collagen.

Embodiment 18

The implantable medical device of embodiment 16, wherein at least one ofsaid first imageable component and said second imageable componentincludes a metallic material.

Embodiment 19

A medical graft device useful for treating a fistula having at least aprimary opening in a bodily structure wall and a fistula tract extendingfrom the primary opening, the medical graft device comprising:

a biocompatible graft body including a capping member and an elongateplug member, the elongate plug member extending from the capping memberand configured to fill at least a portion of the fistula tract; and

a retaining system for retaining the capping member in association withthe plug member, the retaining system including a first retaining memberand a second retaining member, the first retaining member configured forinsertion through an aperture in the capping member and into a generallylongitudinal, first passage in the plug member, the second retainingmember configured for insertion into a generally lateral, second passagein the plug member, wherein the first retaining member and the secondretaining member are configured to engage one another in the plug memberfor maintaining the first retaining member and the second retainingmember in the plug member.

Embodiment 20

The medical graft device of embodiment 19, wherein the first retainingmember and the second retaining member are configured to bond to oneanother in the plug member.

Embodiment 21

The medical graft device of embodiment 19, wherein the first retainingmember and the second retaining member are configured to couple to oneanother in the plug member.

Embodiment 22

The medical graft device of embodiment 19, wherein at least one of thefirst retaining member and the second retaining member includes a pin.

Embodiment 23

The medical graft device of embodiment 19, wherein at least one of thefirst retaining member and the second retaining member includes suturematerial.

Embodiment 24

The medical graft device of embodiment 19, wherein at least one of thefirst retaining member and the second retaining member comprise aresorbable material.

Embodiment 25

A method for treating a fistula having at least a primary opening in abodily structure wall and a fistula tract extending from the primaryopening, the method comprising:

providing a medical graft device, comprising:

-   -   a biocompatible graft body including a capping member and an        actuating member extending from the capping member, the capping        member deformable to a deformed condition including an        externalized radiopaque portion and an internalized radiopaque        portion;    -   wherein the actuating member is configured to extend through the        fistula tract when the graft device is implanted and is        actuatable to convert the capping member to the deformed        condition;

positioning the medical graft device in a patient such that the cappingmember contacts portions of the bodily structure wall adjacent to theprimary opening and the actuating member extends into at least a portionof the fistula tract; and

pulling the actuating member in a direction generally away from theprimary opening so as to convert the capping member to the deformedcondition, wherein the externalized radiopaque portion residesexternally of the fistula tract, and the internalized radiopaque portionresides within the fistula tract and is spaced a distance from theexternalized radiopaque portion.

Embodiment 26

A medical graft device useful for treating a fistula having at least aprimary opening in a bodily structure wall and a fistula tract extendingfrom the primary opening, the medical graft device comprising:

a biocompatible graft body including a capping member and an actuatingmember extending from the capping member, the capping member deformableto a deformed condition including an externalized radiopaque portion andan internalized radiopaque portion, the externalized radiopaque portionconfigured to reside externally of the fistula tract when the graftdevice is implanted and the capping member is deformed, and theinternalized radiopaque portion configured to reside within the fistulatract and be spaced a distance from the externalized radiopaque portionwhen the graft device is implanted and the capping member is deformed;

wherein the actuating member is configured to extend through the fistulatract when the graft device is implanted and is actuatable to convertthe capping member to the deformed condition.

1. A medical graft device useful for treating a fistula having at leasta primary opening in a bodily structure wall and a fistula tractextending from the primary opening, the medical graft device comprising:a biocompatible graft body including a capping member and an elongateplug member, the elongate plug member extending from the capping memberand configured to fill at least a portion of the fistula tract; and aretaining system for retaining the capping member in association withthe plug member, the retaining system including a first retaining memberand a second retaining member, the first retaining member configured forinsertion through an aperture in the capping member and into a generallylongitudinal, first passage in the plug member, the second retainingmember configured for insertion into a generally lateral, second passagein the plug member, wherein the first retaining member and the secondretaining member are configured to engage one another in the plug memberfor maintaining the first retaining member and the second retainingmember in the plug member.
 2. The medical graft device of claim 1,wherein the first retaining member and the second retaining member areconfigured to bond to one another in the plug member.
 3. The medicalgraft device of claim 1, wherein the first retaining member and thesecond retaining member are configured to couple to one another in theplug member.
 4. The medical graft device of claim 1, wherein at leastone of the first retaining member and the second retaining memberincludes a pin.
 5. The medical graft device of claim 1, wherein at leastone of the first retaining member and the second retaining memberincludes suture material.
 6. The medical graft device of claim 1,wherein at least one of the first retaining member and the secondretaining member comprise a resorbable material.
 7. The medical graftdevice of claim 1, wherein the first retaining member includes a pin andthe second retaining member includes a suture material.
 8. The medicalgraft device of claim 7, wherein the suture material is resorbable. 9.The medical graft device of claim 1, wherein the first retaining memberincludes a shank portion extending from a head portion, the shankportion defining an opening for receiving the second retaining memberwhen the first and second retaining members engage one another in theelongate plug member.
 10. The medical graft device of claim 9, whereinthe head portion of the first retaining member has a largercross-sectional dimension than the shank portion of the first retainingmember.
 11. A medical graft device useful for treating a fistula havingat least a primary opening in an alimentary canal wall and a fistulatract extending from the primary opening, the medical graft devicecomprising: a capping member configured to contact portions of thealimentary canal wall adjacent to the primary opening and a retainingsystem for retaining the capping member in association with the primaryopening; wherein the retaining system includes a first retaining memberand a second retaining member, the first retaining member configured forinsertion through an aperture in the capping member and the secondretaining member configured to extend through the a passage defined bythe first retaining member; and wherein the first retaining member is apin and the second retaining member is a suture.
 12. The medical graftdevice of claim 11, wherein the suture material is resorbable.
 13. Themedical graft device of claim 12, wherein the pin is nonresorbable. 14.The medical graft device of claim 11, wherein the pin has a head portionand a shank portion, the head portion having a larger cross-sectionaldimension than the shank portion; and wherein the head portion contactsthe capping member around the aperture and the shank portion of the pinextends through the aperture in the capping member when the cappingmember seals off the primary opening.
 15. The medical graft device ofclaim 11, comprising an elongate plug member extending from the cappingmember and configured to fill at least a portion of the fistula tract;wherein the retaining system retains the capping member in associationwith the plug member.
 16. A medical graft device useful for treating afistula having at least a primary opening in an alimentary canal walland a fistula tract extending from the primary opening, the medicalgraft device comprising: a capping member configured to contact portionsof the alimentary canal wall adjacent to the primary opening and aretaining system for retaining the capping member in association withthe primary opening; wherein the retaining system includes a firstretaining member and a second retaining member, the first retainingmember configured for insertion through an aperture in the cappingmember and the second retaining member configured to extend through thea passage defined by the first retaining member; and wherein the firstretaining member comprises a first material and the second retainingmember comprises a second material different from the first material.17. The medical graft device of claim 16, wherein the second material isresorbable.
 18. The medical graft device of claim 17, wherein the firstmaterial is nonresorbable.
 19. The medical graft device of claim 16,wherein the first retaining member is a pin and the second retainingmember is a suture.
 20. The medical graft device of claim 19, whereinthe pin has a head portion and a shank portion, the head portion havinga larger cross-sectional dimension than the shank portion; and whereinthe head portion contacts the capping member around the aperture and theshank portion of the pin extends through the aperture in the cappingmember when the capping member seals off the primary opening.